Compositions and methods for delivery of frozen particle adhesives

ABSTRACT

Certain embodiments disclosed herein relate to compositions, methods, devices, systems, and products regarding frozen particles. In certain embodiments, the frozen particles include materials at low temperatures. In certain embodiments, the frozen particles provide vehicles for delivery of particular agents. In certain embodiments, the frozen particles are administered to at least one biological tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing date(s) from the following listedapplication(s) (the “Related Applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related Application(s)). All subject matter ofthe Related Applications and of any and all parent, grandparent,great-grandparent, etc. applications of the Related Applications isincorporated herein by reference to the extent such subject matter isnot inconsistent herewith.

RELATED APPLICATIONS

-   -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,671, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,683, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,685, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,686, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,690, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,691, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,684, entitled COMPOSITIONS        AND METHODS FOR THERAPEUTIC DELIVERY WITH FROZEN PARTICLES,        naming Edward S. Boyden, Roderick A. Hyde, Eric C. Leuthardt,        Nathan P. Myhrvold, Elizabeth A. Sweeney and Lowell L. Wood, Jr.        as inventors, filed 31 Oct. 2008, which is currently co-pending,        or is an application of which a currently co-pending application        is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,670, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,664, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,659, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,658, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,665, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,677, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,687, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/290,676, entitled COMPOSITIONS        AND METHODS FOR SURFACE ABRASION WITH FROZEN PARTICLES, naming        Edward S. Boyden, Daniel B. Cook, Roderick A. Hyde, Eric C.        Leuthardt, Nathan P. Myhrvold, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 31 Oct. 2008, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.

For purposes of the USPTO extra-statutory requirements, the presentapplication constitutes a continuation-in-part of U.S. patentapplication Ser. No. 12/383,263, entitled COMPOSITIONS AND METHODS FORDELIVERY OF FROZEN PARTICLE ADHESIVES, naming Edward S. Boyden, DanielB. Cook, Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold,Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed 20 Mar.2009, which is currently co-pending, or is an application of which acurrently co-pending application is entitled to the benefit of thefiling date.

For purposes of the USPTO extra-statutory requirements, the presentapplication constitutes a continuation-in-part of U.S. patentapplication Ser. No. 12/383,260, entitled COMPOSITIONS AND METHODS FORDELIVERY OF FROZEN PARTICLE ADHESIVES, naming Edward S. Boyden, DanielB. Cook, Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold,Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed 20 Mar.2009, which is currently co-pending, or is an application of which acurrently co-pending application is entitled to the benefit of thefiling date.

For purposes of the USPTO extra-statutory requirements, the presentapplication constitutes a continuation-in-part of U.S. patentapplication Ser. No. 12/383,265, entitled COMPOSITIONS AND METHODS FORDELIVERY OF FROZEN PARTICLE ADHESIVES, naming Edward S. Boyden, DanielB. Cook, Roderick A. Hyde, Eric C. Leuthardt, Nathan P. Myhrvold,Elizabeth A. Sweeney and Lowell L. Wood, Jr. as inventors, filed 20 Mar.2009, which is currently co-pending, or is an application of which acurrently co-pending application is entitled to the benefit of thefiling date.

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation or continuation-in-part. Stephen G. Kunin, Benefit ofPrior-Filed Application, USPTO Official Gazette Mar. 18, 2003, availableat http://www.uspto.gov/web/offices/com/sol/og/2003/week11/patbene.htm.The present Applicant Entity (hereinafter “Applicant”) has providedabove a specific reference to the application(s) from which priority isbeing claimed as recited by statute. Applicant understands that thestatute is unambiguous in its specific reference language and does notrequire either a serial number or any characterization, such as“continuation” or “continuation-in-part,” for claiming priority to U.S.patent applications. Notwithstanding the foregoing, Applicantunderstands that the USPTO's computer programs have certain data entryrequirements, and hence Applicant is designating the present applicationas a continuation-in-part of its parent applications as set forth above,but expressly points out that such designations are not to be construedin any way as any type of commentary and/or admission as to whether ornot the present application contains any new matter in addition to thematter of its parent application(s).

SUMMARY

Compositions, methods, systems, and other embodiments related to one ormore frozen particle compositions are described herein. One embodimentincludes a composition comprising one or more frozen particlecompositions including at least one adhesive agent.

In one embodiment, the frozen particle compositions include one or morefrozen particles and at least one adhesive agent.

In one embodiment, a frozen particle composition, comprises: one or morefrozen hydrogen oxide particles including at least one adhesive agent;wherein the one or more frozen hydrogen oxide particles are in one ormore phases including at least one of amorphous solid water, low densityamorphous ice, high density amorphous ice, very high density amorphousice, clathrate ice, hyperquenched glassy water, ice Ic, ice II, ice III,ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, iceXII, ice XIII, ice XIV, or ice XV.

In one embodiment, a frozen particle composition, comprises: one or morefrozen solution particles including at least one adhesive agent; whereinthe one or more frozen solution particles have at least one majordimension of approximately one centimeter or less, approximately onemillimeter or less, approximately one micrometer or less, approximatelyone nanometer or less, or any value therebetween.

In one embodiment, a frozen particle composition comprises: one or morenon-hydrogen oxide frozen solvent particles including at least oneadhesive agent. In one embodiment, the one or more non-hydrogen-oxidefrozen solvent particles include frozen particles of at least one ofacetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,tetrahydrofuran, acetronitrile, acetic acid, n-butanol, isopropanol,n-propanol, hexamethylphosphorotriamide, perfluorohydrocarbon, methanol,ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia,benzene, carbon tetrachloride, acetonitrile, hexane, dichloromethane,methylene chloride, carboxylic acid, saline, standard saline citrate,methane, toluene, chloroform, or diethyl ether. In one embodiment, thefrozen particle composition further comprises at least one ofpolyethylene glycol, Ringer's solution, lactated Ringer's solution,Hartmann's solution, acetated Ringer's solution, phosphate bufferedsolution, TRIS-buffered saline solution, Hank's balanced salt solution,Earle's balanced salt solution, HEPES-buffered saline, dextrose, orglucose. In one embodiment, a frozen particle composition comprises: oneor more non-hydrogen oxide frozen solute particles including at leastone adhesive agent.

In one embodiment, a frozen particle composition, comprises: one or morefrozen adhesive particles; wherein the one or more frozen adhesiveparticles have at least one major dimension of approximately one hundrednanometers or less, approximately one nanometer or less, or any valuetherebetween.

In one embodiment, a frozen particle composition, comprises: one or morefrozen particles of at least one component, wherein the one or morefrozen particles include at least one adhesive agent; and wherein the atleast one component is in a gaseous state at or above 1 bar pressure,and at or above approximately 10° C., approximately 15° C.,approximately 20° C., approximately 25° C., approximately 30° C.,approximately 37° C., approximately 40° C., approximately 45° C., orapproximately 50° C. In one embodiment, the at least one componentincludes one or more of nitrogen, helium, neon, xenon, oxygen, air,krypton, chlorine, bromine, or argon.

In one embodiment, the frozen particle composition includes one or morefrozen particles that exist at about 30° C., about 20° C., about 10° C.,about 5° C., about 0° C., about −10° C., about −20° C., about −30° C.,about −40° C., about −50° C., about −60° C., about −70° C., about −75°C., about −80° C., about −85° C., about −90° C., about −95° C., about−100° C., about −120° C., about −150° C., about −180° C., about −200°C., about −220° C., about −250° C., or any temperature less than ortherebetween.

In one embodiment, the one or more frozen particles have at least onemajor dimension of approximately one centimeter or less, approximatelyone millimeter or less, approximately one micrometer or less,approximately one nanometer or less, or any value therebetween. In oneembodiment, the at least one major dimension includes at least one ofthe radius, diameter, length, width, height, or perimeter.

In one embodiment, the at least one adhesive agent includes at least oneof a monomer, prepolymer, polymer, or copolymer. In one embodiment, theat least one adhesive agent includes at least one monomer of aself-polymerizing agent. In one embodiment, the at least one adhesiveagent includes at least one nontoxic, biocompatible, bioresorbable, orbiodegradable agent. In one embodiment, the at least one adhesive agentis configured to polymerize upon administration to at least onesubstrate. In one embodiment, the at least one adhesive agent isconfigured to polymerize at or above the temperature of the at least onesubstrate. In one embodiment, the at least one adhesive agent isconfigured to polymerize at or above the temperature of at least onebiological tissue. In one embodiment, the at least one adhesive agent isconfigured to polymerize at or above the temperature of at least onesubject.

In one embodiment, the at least one adhesive agent is located in atleast one cavity of the one or more frozen particles. In one embodiment,the at least one cavity includes at least one different phase state thanthe one or more frozen particles. In one embodiment, the at least onecavity includes at least one of a solid, liquid, or gas. In oneembodiment, the at least one cavity includes at least one of a liquid orgas, and the one or more frozen particles include a solid. In oneembodiment, the at least one cavity includes at least one of a solid orliquid, and at least one other cavity includes a solid.

In one embodiment, the at least one adhesive agent includes one or morecomponents that are inactive. In one embodiment, the one or morecomponents are configured to be activated by administration. In oneembodiment, at least two of the one or more components are included inthe same or different frozen particle compositions. In one embodiment,at least two of the one or more components are located in cavities ofthe same or different frozen particle compositions. In one embodiment,at least two of the one or more components each is located in a separatecavity of the same or different frozen particle compositions.

In one embodiment, the at least one agent is configured to modify itsadhesive properties upon administration of the frozen particlecomposition. In one embodiment, the frozen particle composition furtherincludes at least one material that modulates the rate of diffusion ordegradation of the at least one adhesive agent. In one embodiment, theat least one material reduces the rate of diffusion or degradation ofthe at least one adhesive agent. In one embodiment, the at least oneadhesive agent is substantially in the form of at least one of anorganic or inorganic small molecule, clathrate or caged compound,protocell, coacervate, microsphere, Janus particle, proteinoid,laminate, helical rod, liposome, macroscopic tube, niosome, sphingosome,toroid, vesicular tube, vesicle, small unilamellar vesicle, largeunilamellar vesicle, large multilamellar vesicle, multivesicularvesicle, lipid layer, lipid bilayer, micelle, organelle, cell, membrane,nucleic acid, peptide, polypeptide, protein, oligosaccharide,polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, copolymer, cellreceptor, adhesion molecule, cytokine, chemokine, immunoglobulin,antibody, antigen, platelet, extracellular matrix, blood, plasma, cellligand, zwitterionic material, cationic material, oligonucleotide,nanotube, or piloxymer.

In one embodiment, the at least one adhesive agent includes one or moreof an acrylic polymer or copolymer, acrylamide polymer or copolymer,polyacrylic acid, epoxy, urethane, gum arabic, polyester,polyhydroxyalkanoate, poly(L-lactic acid), polyglycolide, polylacticacid, polyether, polyol, polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, polyelectrolyte, maleicpolyelectrolyte, cellulose, resilin, cyanoacrylate, isocyanate, 2-octylcyanoacrylate, 2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate,butyl-2-cyanoacrylate, methyl 2-cyanoacrylate,polyisohexylcyanoacrylate, fibrin, thrombin, fibrinogen, hyaluronate,chitin, Factor XIII, Factor XII, silk, nylon, collagen,glycosaminoglycan, selectin, polyurethane, methacrylate, polysulfide,polyanhydride, polydioxanone, poly-p-dioxanone, albumin, glutaraldehyde,polyethylene glycol, hydrogel, soy, or gelatin.

In one embodiment, the at least one adhesive agent is configured to formone or more of a hydrogen bond, ionic bond, covalent bond, ornon-covalent bond with at least one substrate. In one embodiment, the atleast one adhesive agent includes at least one crosslinking orderivatized agent. In one embodiment, the at least one adhesive agent isconfigured to form a crosslink bond with at least one component of atleast one substrate. In one embodiment, the crosslink bond of the atleast one adhesive agent is configured for modulation by one or more ofa chemical agent, change in pH, change in exposure to air, vacuum,change in moisture content, change in pressure, or change intemperature. In one embodiment, the formation of a crosslink bond of theat least one adhesive agent is configured for modulation by exposure ofthe at least one adhesive agent to one or more of electromagneticenergy, optical energy, thermal energy, laser energy, ionizingradiation, non-ionizing radiation, or sonic energy.

In one embodiment, the frozen particle composition further includes atleast one therapeutic agent. In one embodiment, the at least onetherapeutic agent and the at least one adhesive agent are the sameagent. In one embodiment, the at least one therapeutic agent includes atleast one of an anti-tumor agent, antimicrobial agent, anti-viral agent,analgesic, antiseptic, anesthetic, diagnostic agent, anti-inflammatoryagent, vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotoic promoting factor, enzymaticagent, histatin, honey, calcium alginate, angiogenic factor,anti-angiogenic factor, hormone, vitamin, mineral, nutraceutical,cytokine, chemokine, probiotic, coagulant, anti-coagulant, phage,prodrug, prebiotic, blood sugar stabilizer, smooth muscle cellactivator, epinephrine, adrenaline, neurotoxin, neuro-muscular toxin,Botulinum toxin type A, microbial cell or component thereof, or virus orcomponent thereof.

In one embodiment, the at least one adhesive agent is configured toconvert to at least one therapeutic agent upon administration of the atleast one adhesive agent. In one embodiment, the at least one adhesiveagent configured to undergo one or more of hydration, hydrolysis,hydrogenolysis, condensation, dehydration, or polymerization, uponadministration of the at least one adhesive agent. In one embodiment,the at least one adhesive agent includes a methacrylate. In oneembodiment, the at least one adhesive agent includes at least one ofpoly(N,N-dimethyl-N-(ethoxycarbonylmethyl)-N-[2′-(methacryloyloxy)ethyl]-ammoniumbromide) or poly(sulfobetaine methacrylate).

In one embodiment, the one or more frozen particles include one or moreof hydrogen oxide, nitrogen, oxygen, air, helium, neon, argon, xenon,chlorine, bromine, carbon dioxide, acetone, ethyl acetate, dimethylsulfoxide, dimethyl formamide, dioxane, tetrahydrofuran, acetronitrile,acetic acid, n-butanol, isopropanol, n-propanol,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, benzene,carbon tetrachloride, acetonitrile, hexane, dichloromethane, methylenechloride, carboxylic acid, saline, standard saline citrate, methane,toluene, chloroform, polyethylene glycol, acetic acid, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,standard saline citrate, HEPES-buffered saline, dextrose, glucose,methane, or diethyl ether.

In one embodiment, the one or more frozen particles approximate theshape of at least one of a sphere, bullet, flechette, cone, needle,arrow, spear, diamond, pyramid, cylinder, minie ball, shuttlecock,spiral, bell, pear, crystal, cube, spheroid, tetrahedron, crescent, orpossess a high aspect ratio shape.

In one embodiment, the one or more frozen particles include a pluralityof frozen particles that are approximately uniform in size, shape,weight, or density. In one embodiment, the frozen particle compositionincludes at least one of a frozen liquid, or frozen gas. In oneembodiment, the frozen particle composition includes one or more of asuspension, mixture, solution, sol, clathrate, colloid, emulsion,microemulsion, aerosol, ointment, capsule, powder, tablet, suppository,cream, device, paste, liniment, lotion, ampule, elixir, spray,suspension, syrup, tincture, detection material, polymer, biopolymer,buffer, adjuvant, diluent, lubricant, disintegration agent, suspendingagent, solvent, light-emitting agent, colorimetric agent, glidant,anti-adherent, anti-static agent, surfactant, plasticizer, emulsifyingagent, flavor, gum, sweetener, coating, binder, filler, compression aid,encapsulation aid, preservative, granulation agent, spheronizationagent, stabilizer, adhesive, pigment, sorbent, nanoparticle, or gel.

In one embodiment, the frozen particle composition further includes oneor more reinforcement agents. In one embodiment, at least one of the oneor more reinforcement agents are the same as the at least one adhesiveagent. In one embodiment, the one or more reinforcement agents includeone or more of polyaramid, vinylester matrix, metal, ceramic,fiberglass, cellulose, broad carbide, aromatic polyamide, nylon, silk,rayon, acetate, modacrylic, olefin, acrylic polymer or copolymer,acrylamide polymer or copolymer, polyester, aromatic polyester,poly-lactic acid, vinyon, saran, spandex, vinalon, aromatic nylon,vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell, orlon,zylon, high-performance polyethylene, polypyridobenzimidazole, vectran,acrylonitrile rubber, glass, copper, iron, steel, sodium, potassium,calcium, zinc, manganese, carbon, aluminum, magnesium, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter.

In one embodiment, the frozen particle composition further includes oneor more abrasives.

In one embodiment, the frozen particle composition further includes atleast one of a nanoparticle, detection material, sensor, micro-syringe,or circuit. In one embodiment, the detection material includes at leastone electronic identification device. In one embodiment, the at leastone electronic identification device includes at least one radiofrequency identification device. In one embodiment, the detectionmaterial includes at least one radioactive element. In one embodiment,the at least one radioactive element includes one or more of ³²P, ³⁵S,¹³C, ¹³¹I, ¹⁹¹Ir, ¹⁹²Ir, ¹⁹³Ir, ²⁰¹Tl, or ³H. In one embodiment, thedetection material includes at least one radioactive, luminescent,colorimetric, or odorous substance. In one embodiment, the detectionmaterial includes at least one of a diamagnetic particle, ferromagneticparticle, paramagnetic particle, super paramagnetic contrast agent, orother magnetic particle.

In one embodiment, the frozen particle composition is formulated to beadministered to at least one substrate, including one or more of a cell,tissue, organ, structure, or device. In one embodiment, the frozenparticle composition is formulated to be administered by one or more oftopical administration, oral administration, enteral administration,mucosal administration, percutaneous administration, or parenteraladministration. In one embodiment, the parenteral administrationincludes at least one of intravenous administration, intra-arterialadministration, intracardiac administration, subcutaneousadministration, intraperitoneal administration, or intramuscularadministration. In one embodiment, the frozen particle composition isformulated to be administered by high velocity impact. In oneembodiment, the frozen particle composition is formulated to beadministered by one or more devices.

In one embodiment, the frozen particle composition further includes atleast one pharmaceutically-acceptable carrier or excipient. In oneembodiment, the frozen particle composition further includes one or moreexplosive materials. In one embodiment, at least one of the one or moreexplosive materials are the same as the at least one adhesive agent. Inone embodiment, the one or more explosive materials include at least oneof a carbonate, carbon dioxide, nitroglycerine, acid, base, epoxy,acrylic polymer or copolymer, acrylamide polymer or copolymer, urethane,hypoxyapatite, or a reactive metal. In one embodiment, the at least oneadhesive agent is included as part of a carrier that assists insynthesis or activation of the at least one adhesive agent. In oneembodiment, the at least one adhesive agent is frozen.

In one embodiment, the at least one adhesive agent includes two or morecomponents configured to combine upon administration to at least onesubstrate. In one embodiment, the combination of the two or morecomponents modifies at least one property of the adhesive agent. In oneembodiment, the at least one property includes one or more of initiationof adhesive bond formation, strength of adhesive bond, adhesive bondingtime, bond flexibility, bond biodegradability, bond bioresorbability,bond biocompatibility, or durability of adhesive bond. In oneembodiment, the at least one property includes one or more ofpolymerization of the adhesive agent, or crosslinking of the adhesiveagent. In one embodiment, the frozen particle composition furthercomprises administering two or more frozen particle compositions;wherein at least one administration parameter is different for the twoor more frozen particle compositions.

In one embodiment, the at least one administration parameter includes atleast one of: constitution of the frozen particle composition,formulation of the frozen particle composition, size of the frozenparticle compositions, shape of the frozen particle composition, angleof administration of the frozen particle composition, velocity ofadministration of the frozen particle composition, quantity of frozenparticle compositions administered, rate of administration of more thanone frozen particle composition, spatial location for administration ofthe frozen particle compositions, temporal location for administrationof the frozen particle compositions, method of administration of thefrozen particle compositions, timing of administration of the frozenparticle compositions, modulation of administration of the frozenparticle compositions, deposition of the frozen particle compositions,or rate of deposition of at least one agent included in the frozenparticle compositions.

In one embodiment, a method for providing at least one adhesive agent toat least one substrate comprises: administering at least one frozenparticle composition to at least one substrate, wherein the at least onefrozen particle composition includes one or more frozen hydrogen oxideparticles including at least one adhesive agent; wherein the one or morefrozen hydrogen oxide particles are in one or more phases including atleast one of amorphous solid water, low density amorphous ice, highdensity amorphous ice, very high density amorphous ice, clathrate ice,hyperquenched glassy water, ice Ic, ice II, ice III, ice IV, ice V, iceVI, ice VII, ice VIII, ice IX, ice X, ice XI, ice XII, ice XIII, iceXIV, or ice XV.

In one embodiment, a method for providing at least one adhesive agent toat least one substrate comprises: administering at least one frozenparticle composition to at least one substrate, wherein the at least onefrozen particle composition includes one or more frozen solutionparticles including at least one adhesive agent. In one embodiment, theat least one frozen particle composition is in at least one crystallineor amorphous phase.

In one embodiment, a method for providing at least one adhesive agent toat least one substrate comprises: administering at least one frozenparticle composition to at least one substrate, wherein the at least onefrozen particle composition includes one or more non-hydrogen oxidefrozen solvent particles and at least one adhesive agent. In oneembodiment, the one or more non-hydrogen-oxide frozen solvent particlesinclude frozen particles of at least one of acetone, ethyl acetate,dimethyl sulfoxide, dimethyl formamide, dioxane, tetrahydrofuran,acetronitrile, acetic acid, n-butanol, isopropanol, n-propanol,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, benzene,carbon tetrachloride, acetonitrile, hexane, dichloromethane, methylenechloride, carboxylic acid, saline, standard saline citrate, methane,toluene, chloroform, or diethyl ether. In one embodiment, the methodfurther comprises at least one of polyethylene glycol, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,HEPES-buffered saline, dextrose, or glucose.

In one embodiment, a method for providing at least one adhesive agent toat least one substrate comprises: administering at least one frozenparticle composition to at least one substrate, wherein the at least onefrozen particle composition includes one or more frozen particles of atleast one component, and at least one adhesive agent; and wherein the atleast one component is in a gaseous state at or above 1 bar pressure,and at or above approximately 10° C., approximately 15° C.,approximately 20° C., approximately 25° C., approximately 30° C.,approximately 37° C., approximately 40° C., approximately 45° C., orapproximately 50° C. In one embodiment, the at least one componentincludes one or more of nitrogen, helium, neon, xenon, oxygen, air,krypton, chlorine, bromine, or argon.

In one embodiment, the method includes administering at least one frozenparticle composition that further includes at least onepharmaceutically-acceptable carrier or excipient. In one embodiment, theat least one adhesive agent includes at least one of a monomer,prepolymer, polymer, or copolymer. In one embodiment, the at least oneadhesive agent includes at least one monomer of a self-polymerizingagent. In one embodiment, the at least one adhesive agent includes atleast one nontoxic, biocompatible, bioresorbable, or biodegradableagent. In one embodiment, the at least one adhesive agent is configuredto polymerize upon administration to at least one substrate. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of the at least one substrate. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of at least one biological tissue. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of at least one subject.

In one embodiment, the at least one substrate includes at least onenontoxic, biocompatible, bioresorbable, or biodegradable substrate. Inone embodiment, the substrate includes at least a portion of which isnaturally, artificially, or synthetically derived. In one embodiment,the substrate includes at least a portion of which is geneticallyaltered. In one embodiment, the at least one substrate includes one ormore of a cell, tissue, organ, structure, or device. In one embodiment,the structure includes one or more of a prosthesis, cell matrix, ortissue matrix. In one embodiment, the device includes at least onemechanical or electrical device. In one embodiment, the at least onesubstrate includes at least one implantable substrate. In oneembodiment, the at least one substrate is located in at least one of insitu, in vitro, in vivo, in utero, in planta, in silico, or ex vivo. Inone embodiment, the at least one substrate is transplanted or implantedinto at least one subject. In one embodiment, the at least one substrateis ingested by at least one subject. In one embodiment, the at least onesubstrate includes at least one biological tissue from at least onedonor or recipient. In one embodiment, the at least one donor includesat least one cadaver. In one embodiment, the at least one substrateincludes one or more of skin, scalp, hair, nail, nail bed, teeth, eye,ear, ovary, oviduct, tongue, tonsil, adenoid, liver, bone, pancreas,stomach, blood vessel, blood, lymph, heart, lung, brain, breast, kidney,bladder, urethra, ureter, gall bladder, uterus, prostate, testes, vasdeferens, fallopian tubes, large intestine, small intestine, esophagus,oral cavity, nasal cavity, otic cavity, connective tissue, peritonealtissue, muscle tissue, or adipose tissue. In one embodiment, the atleast one substrate includes one or more of a stalk, stem, leaf, root,plant, or tendril.

In one embodiment, the at least substrate includes at least one cellmass. In one embodiment, the at least one cell mass includes at leastone of a scar, pore, pit, eschar, granuloma, keloid, artheromatousplaque, abscess, pustule, scaling, infected tissue, hair follicle,necrotic tissue, stratum corneum, wrinkle, wound, tumor, skin structure,nevus, cyst, lesion, callus, neoplastic tissue, gangrenous tissue, orcellular deposit. In one embodiment, the at least one cell mass isrelated to at least one blood clot, microorganism accumulation, bloodvessel obstruction, duct obstruction, bowel obstruction, infection,gangrene, connective tissue destruction, tissue or organ damage, injury,white blood cell accumulation, or cancer. In one embodiment, the atleast one substrate includes one or more wounds. In one embodiment, theone or more wounds are located in at least one biological tissue. In oneembodiment, the at least one biological tissue includes at least one ofskin tissue, peritoneal tissue, muscle tissue, eye tissue, an organ,peritoneal tissue, nervous tissue, connective tissue, neoplastic tissue,or bone tissue. In one embodiment, the one or more wounds are located inat least one subject. In one embodiment, the one or more wounds includeat least one of an fracture, incision, laceration, abrasion, irritation,puncture wound, penetration wound, gunshot wound, iatrogenic wound,severing, infection, ulcer, pressure sore, lesion, chemical burn, animalbite, dental caries, first-degree burn, second-degree burn, third-degreeburn, or fourth-degree burn.

In one embodiment, the at least one substrate includes at least aportion of at least one subject. In one embodiment, the at least onesubject includes at least one invertebrate or vertebrate animal. In oneembodiment, the at least one subject includes at least one of a reptile,mammal, amphibian, bird, or fish. In one embodiment, the at least onesubject includes at least one human. In one embodiment, the at least onesubject includes at least one of livestock, pet, undomesticated herdanimal, wild animal, zoo animal, or product animal. In one embodiment,the at least one subject includes at least one of a sheep, goat, frog,dog, cat, rat, mouse, vermin, monkey, duck, horse, cow, pig, chicken,shellfish, fish, turkey, llama, alpaca, bison, buffalo, ape, primate,ferret, wolf, coyote, deer, rabbit, guinea pig, yak, chinchilla, mink,reindeer, camel, fox, raccoon, elk, deer, donkey, or mule.

In one embodiment, the at least one adhesive agent is substantially inthe form of at least one of an organic or inorganic small molecule,clathrate or caged compound, protocell, coacervate, microsphere, Janusparticle, proteinoid, laminate, helical rod, liposome, macroscopic tube,niosome, sphingosome, toroid, vesicular tube, vesicle, small unilamellarvesicle, large unilamellar vesicle, large multilamellar vesicle,multivesicular vesicle, lipid layer, lipid bilayer, micelle, organelle,cell, membrane, nucleic acid, peptide, polypeptide, protein,oligosaccharide, polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, copolymer, cellreceptor, adhesion molecule, cytokine, chemokine, immunoglobulin,antibody, antigen, platelet, extracellular matrix, blood, plasma, cellligand, zwitterionic material, cationic material, oligonucleotide,nanotube, or piloxymer.

In one embodiment, the at least one adhesive agent includes one or moreof an acrylic polymer or copolymer, acrylamide polymer or copolymer,polyacrylic acid, epoxy, urethane, gum arabic, polyester,polyhydroxyalkanoate, poly(L-lactic acid), polyglycolide, polylacticacid, polyether, polyol, polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, polyelectrolyte, maleicpolyelectrolyte, cellulose, resilin, cyanoacrylate, isocyanate, 2-octylcyanoacrylate, 2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate,butyl-2-cyanoacrylate, methyl 2-cyanoacrylate,polyisohexylcyanoacrylate, fibrin, thrombin, fibrinogen, hyaluronate,chitin, Factor XIII, Factor XII, silk, nylon, collagen,glycosaminoglycan, selectin, polyurethane, methacrylate, polysulfide,polyanhydride, polydioxanone, poly-p-dioxanone, albumin, glutaraldehyde,polyethylene glycol, hydrogel, soy, or gelatin.

In one embodiment, the at least one adhesive agent includes one or morecomponents that are inactive. In one embodiment, the one or morecomponents are configured to be activated by administration. In oneembodiment, administering at least one frozen particle composition to atleast one substrate includes accelerating, propelling, or ejecting thefrozen particle composition toward the at least one substrate. In oneembodiment, administering the at least one frozen particle compositionto at least one substrate includes propelling, ejecting, or acceleratingthe at least one frozen particle composition toward the at least onesubstrate at a predetermined angle, predetermined velocity, orpredetermined rate of administration. In one embodiment, the methodfurther includes varying the rate, velocity, or angle at which the atleast one frozen particle composition is administered to at least onesubstrate. In one embodiment, administering the at least one frozenparticle composition to at least one substrate includes propelling,ejecting, or accelerating a plurality of frozen particle compositionstoward the at least one substrate. In one embodiment, two or more of theplurality of frozen particle compositions include two or more adhesiveagents that are configured to physically or chemically bind uponadministration. In one embodiment, administering the at least one frozenparticle composition to at least one substrate includes contacting theat least one substrate with the at least one frozen particlecomposition. In one embodiment, administering the at least one frozenparticle composition to at least one substrate includes contacting theat least one substrate with the at least one adhesive agent. In oneembodiment, administering the at least one frozen particle compositionoccurs prior to, during, or subsequent to surgery.

In one embodiment, the method further includes administering to the atleast one substrate at least one of a nanoparticle, detection material,sensor, micro-syringe, or circuit. In one embodiment, the detectionmaterial is intermixed with the at least one frozen particlecomposition. In one embodiment, the detection material is located in theat least one frozen particle composition. In one embodiment, thedetection material is located in the one or more frozen hydrogen oxideparticles. In one embodiment, the detection material includes at leastone electronic identification device. In one embodiment, the at leastone electronic identification device includes at least one radiofrequency identification device. In one embodiment, the detectionmaterial includes at least one radioactive element. In one embodiment,the at least one radioactive element includes one or more of ³²P, ³⁵S,¹³C, ¹³¹I, ¹⁹¹Ir, ¹⁹²Ir, ¹⁹³Ir, ²⁰¹Tl, ³H. In one embodiment, thedetection material includes at least one luminescent, radioactive,colorimetric, or odorous substance. In one embodiment, the detectionmaterial includes at least one of a diamagnetic particle, ferromagneticparticle, paramagnetic particle, super paramagnetic contrast agent, orother magnetic particle.

In one embodiment, the method includes one or more frozen particlecomposition that further includes one or more of hydrogen oxide,nitrogen, oxygen, air, helium, neon, argon, xenon, chlorine, bromine,carbon dioxide, acetone, ethyl acetate, dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, acetronitrile, acetic acid,n-butanol, isopropanol, n-propanol, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, benzene, carbon tetrachloride,acetonitrile, hexane, dichloromethane, methylene chloride, carboxylicacid, saline, standard saline citrate, methane, toluene, chloroform,polyethylene glycol, acetic acid, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, methane, or diethyl ether.

In one embodiment, the method includes at least one frozen particlecomposition that further includes one or more of a reinforcement agent,abrasive, explosive material, or biological remodeling agent.

In one embodiment, the at least one adhesive agent includes a detectablestate that varies with its adhesive state. In one embodiment, the atleast one adhesive agent includes one or more epoxy adhesive, acrylicadhesive, urethane adhesive, polyurethane adhesive, silicone adhesive,cationic adhesive, anerobic adhesive, urethane acrylate, polyesteracrylate, methyacrylate, or cyanoacrylate. In one embodiment, the atleast one adhesive agent includes at least one α-cyanoacrylate and afluorescent compound including at least one of a bis-benzoxazolylcompound, pyrylium salt, quantum dot, or coumarin compound. In oneembodiment, the at least one adhesive agent includes an α-cyanoacrylateand 2,5-bis-(5-tert-butyl-2-benzoxasolyl)-thiophene. In one embodiment,the at least one adhesive agent further includes one or more of a basecomponent, initiator component, or activator component. In oneembodiment, the at least one adhesive agent further includes at leastone curing component. In one embodiment, the at least one adhesive agentincludes at least one photopolymerizable adhesive, photocurableadhesive, thermal curable adhesive, free radical curable adhesive, oraerobic curable adhesive. In one embodiment, the at least one adhesiveagent includes one or more adhesive agent configured to polymerize uponexposure to infrared light, ultraviolet light, x-ray, visible light, orother electromagnetic radiation. In one embodiment, the adhesive agentincludes at least one dye coinitiator.

In one embodiment, the at least one dye coinitiator includes at leastone of a bis-benzoxazolyl compound, pyrylium salt, QTX, safranine O,fluorescein, eosin yellow, eosin Y, eosin B, ethyl eosin, eosin bluish,erythrosine B, erythrosine yellowish blend, toluidine blue,4′,5′-dibromofluorescein, Rose Bengal B, cyanine, pyronin GY, cresylviolet, brilliant green, lissamine green BN, rhodamine B, methyleneblue, crystal violet, phosphine oxide, or coumarin compound.

In one embodiment, the at least one adhesive agent includes one or morecomponents that are inactive. In one embodiment, the one or morecomponents are configured to be activated by administration. In oneembodiment, the at least one adhesive agent includes two or morecomponents configured to combine upon administration to at least onesubstrate. In one embodiment, the combination of the two or morecomponents modifies at least one property of the adhesive agent. In oneembodiment, the at least one property includes one or more of initiationof adhesive bond formation, strength of adhesive bond, adhesive bondingtime, bond flexibility, bond biodegradability, bond bioresorbability,bond biocompatibility, or durability of adhesive bond. In oneembodiment, the at least one property includes one or more ofpolymerization of the adhesive agent, or cross-linking of the adhesiveagent.

In one embodiment, the method further comprises administering two ormore frozen particle compositions; wherein at least one administrationparameter is different for the two or more frozen particle compositions.In one embodiment, the at least one administration parameter includes atleast one of: constitution of the frozen particle composition,formulation of the frozen particle composition, size of the frozenparticle compositions, shape of the frozen particle composition, angleof administration of the frozen particle composition, velocity ofadministration of the frozen particle composition, quantity of frozenparticle compositions administered, rate of administration of more thanone frozen particle composition, spatial location for administration ofthe frozen particle compositions, temporal location for administrationof the frozen particle compositions, method of administration of thefrozen particle compositions, timing of administration of the frozenparticle compositions, modulation of administration of the frozenparticle compositions, deposition of the frozen particle compositions,or rate of deposition of at least one agent included in the frozenparticle compositions.

In one embodiment, a method of maintaining the approximation of tissueof at least one wound of a subject comprises: administering at least onefrozen particle composition to at least one wound of a subject for atime sufficient to maintain the approximation of tissue of the at leastone wound; wherein the at least one frozen particle composition includesone or more frozen hydrogen oxide particles including at least oneadhesive, and wherein the one or more frozen hydrogen oxide particleshave one or more phases including at least one of amorphous solid water,low density amorphous ice, high density amorphous ice, very high densityamorphous ice, clathrate ice, hyperquenched glassy water, ice Ic, iceII, ice III, ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X,ice XI, ice XII, ice XIII, ice XIV, or ice XV.

In one embodiment, a method of maintaining the approximation of tissueof the at least one wound of a subject comprises: administering at leastone frozen particle composition to at least one wound of a subject for atime sufficient to maintain the approximation of tissue of the at leastone wound; wherein the at least one frozen particle composition includesone or more frozen solution particles including at least one adhesiveagent. In one embodiment, the at least one frozen particle compositionis in at least one crystalline or amorphous phase.

In one embodiment, a method of maintaining the approximation of tissueof at least one wound of a subject comprises: administering at least onefrozen particle composition to at least one wound of a subject for atime sufficient to maintain the approximation of tissue of the at leastone wound; wherein the at least one frozen particle composition includesone or more non-hydrogen oxide frozen solvent particles and at least oneadhesive agent. In one embodiment, the one or more non-hydrogen-oxidefrozen solvent particles include frozen particles of at least one ofacetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,tetrahydrofuran, acetronitrile, acetic acid, n-butanol, isopropanol,n-propanol, hexamethylphosphorotriamide, perfluorohydrocarbon, methanol,ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia,benzene, carbon tetrachloride, acetonitrile, hexane, dichloromethane,methylene chloride, carboxylic acid, saline, standard saline citrate,methane, toluene, chloroform, or diethyl ether. In one embodiment, themethod includes one or more frozen particle compositions furthercomprising at least one of polyethylene glycol, Ringer's solution,lactated Ringer's solution, Hartmann's solution, acetated Ringer'ssolution, phosphate buffered solution, TRIS-buffered saline solution,Hank's balanced salt solution, Earle's balanced salt solution,HEPES-buffered saline, dextrose, or glucose.

In one embodiment, a method of maintaining the approximation of tissueof at least one wound of a subject comprises: administering at least onefrozen particle composition to at least one wound of a subject for atime sufficient to maintain the approximation of tissue of the at leastone wound; wherein the at least one frozen particle composition includesone or more frozen particles of at least one component, and at least oneadhesive agent; and wherein the at least one component is in a gaseousstate at or above 1 bar pressure, and at or above approximately 10° C.,approximately 15° C., approximately 20° C., approximately 25° C.,approximately 30° C., approximately 37° C., approximately 40° C.,approximately 45° C., or approximately 50° C. In one embodiment, the atleast one component includes one or more of nitrogen, helium, neon,xenon, oxygen, air, krypton, chlorine, bromine, or argon.

In one embodiment, the at least one frozen particle composition furtherincludes at least one pharmaceutically-acceptable carrier or excipient.In one embodiment, the at least one adhesive agent includes at least oneof a monomer, prepolymer, polymer, or copolymer. In one embodiment, theat least one adhesive agent includes at least one monomer of aself-polymerizing agent.

In one embodiment, the at least one adhesive agent is configured topolymerize upon administration to the at least one wound. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of the at least one wound. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of at least one biological tissue. In oneembodiment, the at least one adhesive agent is configured to polymerizeat or above the temperature of at least one subject. In one embodiment,the at least one wound is located in one or more of a cell, tissue, ororgan. In one embodiment, the tissue or organ includes at least one ofskin tissue, muscle tissue, eye tissue, an organ, nervous tissue,peritoneal tissue, connective tissue, neoplastic tissue, or bone tissue.

In one embodiment, the subject includes at least one invertebrate orvertebrate animal. In one embodiment, the subject includes at least oneof a reptile, mammal, amphibian, bird, or fish. In one embodiment, thesubject includes at least one human. In one embodiment, the subjectincludes at least one of livestock, pet, undomesticated herd animal, zooanimal, wild animal, or product animal. In one embodiment, the subjectincludes at least one of a sheep, goat, frog, dog, cat, rat, mouse,vermin, monkey, duck, horse, cow, pig, chicken, shellfish, fish, turkey,llama, alpaca, bison, buffalo, ape, primate, ferret, wolf, coyote, deer,rabbit, guinea pig, yak, chinchilla, mink, reindeer, camel, fox,raccoon, elk, deer, donkey, or mule.

In one embodiment, the at least one adhesive agent is substantially inthe form of at least one of an organic or inorganic small molecule,clathrate or caged compound, protocell, coacervate, microsphere, Janusparticle, proteinoid, laminate, helical rod, liposome, macroscopic tube,niosome, sphingosome, toroid, vesicular tube, vesicle, small unilamellarvesicle, large unilamellar vesicle, large multilamellar vesicle,multivesicular vesicle, lipid layer, lipid bilayer, micelle, organelle,cell, membrane, nucleic acid, peptide, polypeptide, protein,oligosaccharide, polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, copolymer, cellreceptor, adhesion molecule, cytokine, chemokine, immunoglobulin,antibody, antigen, platelet, extracellular matrix, blood, plasma, cellligand, zwitterionic material, cationic material, oligonucleotide,nanotube, or piloxymer.

In one embodiment, the at least one adhesive agent includes one or moreof an acrylic polymer or copolymer, acrylamide polymer or copolymer,polyacrylic acid, epoxy, urethane, gum arabic, polyester,polyhydroxyalkanoate, poly(L-lactic acid), polyglycolide, polylacticacid, polyether, polyol, polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, polyelectrolyte, maleicpolyelectrolyte, cellulose, resilin, cyanoacrylate, isocyanate, 2-octylcyanoacrylate, 2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate,butyl-2-cyanoacrylate, methyl 2-cyanoacrylate,polyisohexylcyanoacrylate, fibrin, thrombin, fibrinogen, hyaluronate,chitin, Factor XIII, Factor XII, silk, nylon, collagen,glycosaminoglycan, selectin, polyurethane, methacrylate, polysulfide,polyanhydride, polydioxanone, poly-p-dioxanone, albumin, glutaraldehyde,polyethylene glycol, hydrogel, soy, or gelatin.

In one embodiment, the at least one adhesive agent includes one or morecomponents that are inactive. In one embodiment, the one or morecomponents are configured to be activated by administration. In oneembodiment, administering at least one frozen particle composition to atleast one wound includes accelerating, propelling, or ejecting thefrozen particle composition toward the at least one wound. In oneembodiment, administering the at least one frozen particle compositionto at least one wound includes propelling, ejecting, or accelerating theat least one frozen particle composition toward the at least one woundat a predetermined angle, predetermined velocity, or predetermined rateof administration. In one embodiment, the method further includesvarying the rate, velocity, or angle at which the at least one frozenparticle composition is administered to at least one wound. In oneembodiment, administering at least one frozen particle composition to atleast one wound includes propelling, ejecting, or accelerating aplurality of frozen particle compositions toward the at least one wound.

In one embodiment, two or more of the plurality of frozen particlecompositions include two or more adhesive agents configured tophysically or chemically bind upon administration. In one embodiment,administering at least one frozen particle composition to at least onewound includes contacting the at least one wound with the at least onefrozen particle composition. In one embodiment, administering at leastone frozen particle composition to at least one wound includescontacting the at least one wound with the at least one adhesive agent.In one embodiment, administering the at least one frozen particlecomposition occurs prior to, during, or subsequent to surgery. In oneembodiment, the at least one wound is located in at least one of insitu, in vitro, in vivo, in utero, in planta, in silico, or ex vivo. Inone embodiment, the at least one wound is located in one or more ofskin, scalp, hair, nail, nail bed, teeth, eye, ear, ovary, oviduct,tongue, tonsil, adenoid, liver, bone, pancreas, stomach, blood vessel,blood, lymph, heart, lung, brain, breast, kidney, bladder, urethra,ureter, gall bladder, uterus, prostate, testes, vas deferens, fallopiantubes, large intestine, small intestine, esophagus, oral cavity, nasalcavity, otic cavity, connective tissue, muscle tissue, peritonealtissue, or adipose tissue. In one embodiment, the at least one wound isrelated to at least one blood clot, microorganism accumulation, bloodvessel obstruction, duct obstruction, bowel obstruction, infection,gangrene, connective tissue destruction, tissue or organ damage, injury,white blood cell accumulation, or cancer. In one embodiment, the atleast one wound includes at least one of an incision, fracture,irritation, laceration, abrasion, puncture wound, penetration wound,gunshot wound, iatrogenic wound, severing, infection, ulcer, pressuresore, lesion, chemical burn, animal bite, dental caries, first-degreeburn, second-degree burn, third-degree burn, or fourth-degree burn.

In one embodiment, the method further includes administering to the atleast one substrate at least one of a nanoparticle, detection material,sensor, micro-syringe, or circuit. In one embodiment, the detectionmaterial is intermixed with the at least one frozen particlecomposition. In one embodiment, the detection material is located in theat least one frozen particle composition. In one embodiment, thedetection material is located in the one or more frozen particles. Inone embodiment, the detection material includes at least one electronicidentification device. In one embodiment, the at least one electronicidentification device includes at least one radio frequencyidentification device. In one embodiment, the detection materialincludes at least one radioactive element. In one embodiment, the atleast one radioactive element includes one or more of ³²P, ³⁵S, ¹³C,¹³¹I, ¹⁹¹Ir, ¹⁹²Ir, ¹⁹³Ir, ²⁰¹Tl, or ³H. In one embodiment, thedetection material includes at least one radioactive, luminescent,colorimetric, or odorous substance. In one embodiment, the detectionmaterial includes at least one of a diamagnetic particle, ferromagneticparticle, paramagnetic particle, super paramagnetic contrast agent, orother magnetic particle. In one embodiment, the at least one frozenparticle composition includes at least one of hydrogen oxide, nitrogen,oxygen, air, helium, neon, argon, xenon, chlorine, bromine, carbondioxide, acetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide,dioxane, tetrahydrofuran, acetronitrile, acetic acid, n-butanol,isopropanol, n-propanol, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, benzene, carbon tetrachloride,acetonitrile, hexane, dichloromethane, methylene chloride, carboxylicacid, saline, standard saline citrate, methane, toluene, chloroform,polyethylene glycol, acetic acid, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, methane, or diethyl ether.

In one embodiment, the at least one frozen particle composition furtherincludes one or more of a reinforcement agent, abrasive, explosivematerial, or biological remodeling agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates particular phases of hydrogen oxide.

FIG. 2 illustrates the density of hydrogen oxide at various pressurepoints.

FIG. 3 illustrates particular phases of hydrogen oxide at variouspressure and temperature points.

FIG. 4 illustrates particular phases of hydrogen oxide at variouspressure and temperature points.

FIG. 5 illustrates the strength of hydrogen oxide samples reinforcedwith fiberglass or kaolin.

FIG. 6 illustrates the strength of hydrogen oxide samples reinforcedwith a reinforcement agent.

FIG. 7 illustrates a partial view of a method 700 that includesgenerating at least one response.

FIG. 8 illustrates a partial view of FIG. 7 in which embodiments may beimplemented.

FIG. 9 illustrates a partial view of FIG. 7 in which embodiments may beimplemented.

FIG. 10 illustrates a partial view of a method 1000 that includesgenerating at least one response.

FIG. 11 illustrates a partial view of FIG. 10 in which embodiments maybe implemented.

FIG. 12 illustrates a partial view of FIG. 10 in which embodiments maybe implemented.

FIG. 13 illustrates a partial view of a system 1300 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 14 illustrates a partial view of FIG. 13 in which embodiments maybe implemented.

FIG. 15 illustrates a partial view of FIG. 13 in which embodiments maybe implemented.

FIG. 16 illustrates a partial view of a system 1600 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 17 illustrates a partial view of a computer program product 1700for executing a computing process on a computing device.

FIG. 18 illustrates a partial view of a computer program product 1800for executing a computing process on a computing device.

FIG. 19 illustrates a partial view of a computer program product 1900for executing a computing process on a computing device.

FIG. 20 illustrates a partial view of a computer program product 2000for executing a computing process on a computing device.

FIG. 21 illustrates a partial view of a computer program product 2100for executing a computing process on a computing device.

FIG. 22 illustrates a partial view of a computer program product 2200for executing a computing process on a computing device.

FIG. 23 illustrates a partial view of a method 2300 that includesgenerating at least one response.

FIG. 24 illustrates a partial view FIG. 23 in which embodiments may beimplemented.

FIG. 25 illustrates a partial view FIG. 23 in which embodiments may beimplemented.

FIG. 26 illustrates a partial view of a method 2600 that includesgenerating at least one response.

FIG. 27 illustrates a partial view of FIG. 26 in which embodiments maybe implemented.

FIG. 28 illustrates a partial view of FIG. 26 in which embodiments maybe implemented.

FIG. 29 illustrates a partial view of a system 2900 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 30 illustrates a partial view of FIG. 29 in which embodiments maybe implemented.

FIG. 31 illustrates a partial view of a system 3100 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 32 illustrates a partial view of FIG. 31 in which embodiments maybe implemented.

FIG. 33 illustrates a partial view of a system 3300 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 34 illustrates a partial view of FIG. 33 in which embodiments maybe implemented.

FIG. 35 illustrates a partial view of FIG. 33 in which embodiments maybe implemented.

FIG. 36 illustrates a partial view of a system 3600 that includes acomputer program for executing a computing process on a computingdevice.

FIG. 37 illustrates a partial view of a method 3700 in which embodimentsmay be implemented.

FIG. 38 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 39 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 40 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 41 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 42 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 43 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 44 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 45 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 46 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 47 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 48 illustrates a partial view of FIG. 37 in which embodiments maybe implemented.

FIG. 49 illustrates a partial view of a method 4900 in which embodimentsmay be implemented.

FIG. 50 illustrates a partial view of FIG. 49 in which embodiments maybe implemented.

FIG. 51 illustrates a partial view of FIG. 49 in which embodiments maybe implemented.

FIG. 52 illustrates a partial view of FIG. 49 in which embodiments maybe implemented.

FIG. 53 illustrates a partial view of FIG. 49 in which embodiments maybe implemented.

FIG. 54 illustrates a partial view of a method 5400 in which embodimentsmay be implemented.

FIG. 55 illustrates a partial view of FIG. 54 in which embodiments maybe implemented.

FIG. 56 illustrates a partial view of FIG. 54 in which embodiments maybe implemented.

FIG. 57 illustrates a partial view of FIG. 54 in which embodiments maybe implemented.

FIG. 58 illustrates a partial view of FIG. 54 in which embodiments maybe implemented.

FIG. 59 illustrates a partial view of a method 5900 in which embodimentsmay be implemented.

FIG. 60 illustrates a partial view of a method 6000 in which embodimentsmay be implemented.

FIG. 61 illustrates a partial view of FIG. 60 in which embodiments maybe implemented.

FIG. 62 illustrates a partial view of FIG. 60 in which embodiments maybe implemented.

FIG. 63 illustrates a partial view of FIG. 60 in which embodiments maybe implemented.

FIG. 64 illustrates a partial view of FIG. 60 in which embodiments maybe implemented.

FIG. 65 illustrates a partial view of FIG. 60 in which embodiments maybe implemented.

FIG. 66 illustrates a partial view of a method 6600 in which embodimentsmay be implemented.

FIG. 67 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 68 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 69 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 70 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 71 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 72 illustrates a partial view of FIG. 66 in which embodiments maybe implemented.

FIG. 73 illustrates a partial view of a system 7300 in which embodimentsmay be implemented.

FIG. 74 illustrates a partial view of FIG. 73 in which embodiments maybe implemented.

FIG. 75 illustrates a partial view of a system 7510 in which embodimentsmay be implemented.

FIG. 76 illustrates a partial view of FIG. 75 in which embodiments maybe implemented.

FIG. 77 illustrates a partial view of a system 7700 in which embodimentsmay be implemented.

FIG. 78 illustrates a partial view of a computer program product 7800 inwhich embodiments may be implemented.

FIG. 79 illustrates a partial view of a system 7900 in which embodimentsmay be implemented.

FIG. 80 illustrates a partial view of a system 8000 in which embodimentsmay be implemented.

FIG. 81 illustrates a partial view of FIG. 80 in which embodiments maybe implemented.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments can be utilized, and other changes can be made,without departing from the spirit or scope of the subject matterpresented here.

In one embodiment, at least one frozen particle composition (includingtherapeutic compositions), device, system, product, machine, or methoddisclosed herein relates to making, administering, or utilizing one ormore frozen particle compositions for various purposes.

Frozen Particles

In one embodiment, the one or more frozen particle compositions includeone or more frozen particles and optionally, at least one other agent.In one embodiment, the at least one agent includes at least one of atherapeutic agent, reinforcement agent, abrasive, biological remodelingagent, explosive material, or adhesive agent. In one embodiment, thefrozen particle composition includes at least one material thatmodulates the rate of diffusion or degradation of the at least oneagent. In one embodiment, the at least one material reduces the rate ofdiffusion or degradation of the at least one agent.

In one embodiment, the at least one agent includes or is substantiallyin the form of at least one of substantially in the form of at least oneof an organic or inorganic small molecule, clathrate or caged compound,protocell, coacervate, microsphere, Janus particle, proteinoid,laminate, helical rod, liposome, macroscopic tube, niosome, sphingosome,toroid, vesicular tube, vesicle, small unilamellar vesicle, largeunilamellar vesicle, large multilamellar vesicle, multivesicularvesicle, lipid layer, lipid bilayer, micelle, organelle, cell, membrane,nucleic acid, peptide, polypeptide, protein, oligosaccharide,polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, copolymer, cellreceptor, adhesion molecule, cytokine, chemokine, immunoglobulin,antibody, antigen, platelet, extracellular matrix, blood, plasma, cellligand, zwitterionic material, cationic material, oligonucleotide,nanotube, or piloxymer.

In one embodiment, the one or more frozen particle compositions includeone or more frozen particles made up of at least one frozen constituent.In one embodiment, the one or more frozen particle compositions includeone or more frozen particles including a single frozen constituent. Inone embodiment, the one or more frozen particles include multiple frozenconstituents. In one embodiment, the one or more frozen particlesinclude frozen solute particles, and optionally, at least one agent. Inone embodiment, the one or more frozen particles include non-hydrogenoxide frozen solute particles, and optionally, at least one agent. Inone embodiment, the one or more frozen particles include frozen solventparticles, and optionally, at least one agent. In one embodiment, theone or more frozen particles include non-hydrogen oxide frozen solventparticles and optionally, at least one agent. In one embodiment, the oneor more frozen particles include frozen solution particles, andoptionally, at least one agent. In one embodiment, a compositionincludes one or more frozen solution particles and at least one agent;wherein the frozen particle composition is in at least one crystallineor amorphous phase.

In one embodiment, the one or more frozen particles include frozenparticles of at least one component that is in a gaseous state at orabove 1 bar pressure and at or above approximately 10° C., approximately15° C., approximately 20° C., approximately 25° C., approximately 30°C., approximately 35° C., approximately 37° C., approximately 40° C.,approximately 45° C., approximately 50° C. In one embodiment, the one ormore frozen particles include one or more frozen hydrogen oxideparticles.

In one embodiment, the frozen particle composition includes one or morefrozen particles including at least one of hydrogen oxide, helium, neon,krypton, argon, xenon, nitrogen, chlorine, bromine, methane, oxygen,air, carbon dioxide, polyethylene glycol, acetone, ethyl acetate,dimethyl sulfoxide, dimethyl formamide, dioxane, tetrahydrofuran,acetronitrile, acetic acid, n-butanol, isopropanol, n-propanol,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, benzene,carbon tetrachloride, acetonitrile, hexane, dichloromethane, methylenechloride, carboxylic acid, saline, standard saline citrate, methane,toluene, chloroform, polyethylene glycol, acetic acid, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,standard saline citrate, HEPES-buffered saline, dextrose, glucose,methane, diethyl ether, or any solution, suspension, mixture, or colloidincluding one or more thereof.

In one embodiment, the frozen particle composition includes one or morefrozen particles, wherein the frozen hydrogen oxide particle is in oneor more phases including at least one of amorphous solid water, lowdensity amorphous ice, high density amorphous ice, very high densityamorphous ice, clathrate ice, hyperquenched glassy water, ice Ic, iceII, ice III, ice IV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X,ice XI, ice XII, ice XIII, ice XIV, or ice XV.

In one embodiment, the frozen particle composition includes one or morefrozen solution particles, optionally including at least one agent;wherein the one or more frozen solution particles have at least onemajor dimension of approximately one centimeter or less, approximatelyone millimeter or less, approximately one micrometer or less,approximately one nanometer or less, or any value therebetween.

In one embodiment, at least one of the constituents of the one or morefrozen particle compositions is frozen. In one embodiment, all of theconstituents of the one or more frozen particle compositions are frozen.In one embodiment, the one or more frozen particle compositions have atleast one major dimension of approximately one decimeter or less,approximately one centimeter or less, approximately one millimeter orless, approximately one micrometer or less, approximately one nanometeror less, approximately one picometer or less, or any value therebetween.In one embodiment, a plurality of frozen particle compositions isdelivered or administered, and the plurality includes at least twosubsets of frozen particle compositions which can be differentiatedbased on size. In one embodiment, a plurality of frozen particlecompositions includes at least one subset of frozen particlecompositions that have at least one major dimension of approximately tenmicrometers or less. In one embodiment, the at least one major dimensionof the one or more frozen particle compositions includes at least one ofradius, diameter, length, width, height, or perimeter.

In one embodiment, the one or more frozen particle compositionsapproximate the shape of at least one of a sphere, bullet, flechette,cone, needle, arrow, spear, diamond, pyramid, cylinder, mini ball,shuttlecock, spiral, bell, pear, crystal, cube, spheroid, tetrahedron,crescent, or high aspect ratio shape. The size, shape, weight, ordensity, as well as other physical parameters of the one or more frozenparticle compositions can be adjusted according to a frozen particlecomposition, or desired goal in utilizing the frozen particlecomposition(s). In one embodiment, the one or more frozen particlecompositions include a plurality of frozen particles that areapproximately uniform with regard to size, shape, weight, or density. Inone embodiment, the one or more frozen particle compositions include anarray of different sizes, shapes, weights, or densities.

In one embodiment, the one or more frozen particle compositions exist atabout 30° C., about 20° C., about 10° C., about 5° C., about 0° C.,about −10° C. about −20° C., about −30° C., about −40° C., about −50°C., about −60° C., about −70° C., about −75° C., about −80° C., about−85° C., about −90° C., about −95° C., about −100° C., about −120° C.,about −150° C., about −180° C., about −200° C., about −220° C., about−250° C., or any temperature less than or therebetween.

In one embodiment, the frozen particle composition includes at least oneof a solid, liquid, or gas. In one embodiment, the frozen particlecomposition includes at least one of a frozen liquid, or frozen gas. Inone embodiment, the frozen particle composition includes at least onepharmaceutically acceptable carrier or excipient. In one embodiment, thefrozen particle composition is formulated to be administered by one ormore of topical administration, oral administration, enteraladministration, mucosal administration, percutaneous administration, orparenteral administration. In one embodiment, parenteral administrationincludes at least one of intravenous administration, intra-arterialadministration, intracardiac administration, subcutaneousadministration, intraperitioneal administration, or intramuscularadministration. In one embodiment, the frozen particle composition isformulated to be administered by high velocity impact. In oneembodiment, the frozen particle composition is formulated to beadministered by one or more devices.

In one embodiment, the frozen particle composition includes one or moreof a suspension, mixture, solution, sol, clathrate, colloid, emulsion,microemulsion, aerosol, ointment, capsule, powder, tablet, suppository,cream, device, paste, resin, liniment, lotion, ampule, elixir, spray,suspension, syrup, tincture, detection material, polymer, biopolymer,buffer, adjuvant, diluent, lubricant, disintegration agent, suspendingagent, solvent, light-emitting agent, colorimetric agent, glidant,anti-adherent, anti-static agent, surfactant, plasticizer, emulsifyingagent, flavor, gum, sweetener, coating, binder, filler, compression aid,encapsulation aid, preservative, granulation agent, spheronizationagent, stabilizer, adhesive, pigment, sorbent, nanoparticle, or gel.

In one embodiment, the one or more frozen particle compositions includefrozen hydrogen oxide particles. Frozen hydrogen oxide, or typical waterice, exists in several non-crystalline forms. Each of these forms hasspecific physical characteristics such as density and vibrationalspectra. Some examples of frozen hydrogen oxide phase transformationsare shown in FIG. 1. (See e.g., Chaplin, the worldwide web atlsbu.ac.uk/water; Ivanov et al., Russian J. Gen. Chem. vol. 75, pp.1851-1856 (2005), each of which is incorporated herein by reference).

Hydrogen oxide (water) has many frozen phases (ices), includingcrystalline and non-crystalline phases. The crystalline phases generallyhave the common structure of having hydrogen bonds to four neighboringwater molecules, such as two hydrogen atoms near each oxygen atom.Structural data on the known frozen hydrogen oxide polymorphs are shownin Table I, with two known phases of ice XI. (See, e.g., Chaplin, Ibid;and Zheligovskaya, et al., Russian Chem. Rev. 75, pp. 57-76, 2006, eachof which is incorporated herein by reference).

TABLE I Structural Data on the Ice Polymorphs Dielectric Density,constant, Ice polymorph g/cm³ Protons Crystal Symmetry ε_(S) NotesHexagonal ice, Ih 0.92 disordered Hexagonal One C₆ 97.5 Cubic ice, Ic0.92 disordered Cubic four C₃ LDA, Ia 0.94 disordered Non- As prepared,crystalline can be mixtures of several types HAD 1.17 disordered Non- Asprepared, crystalline can be mixtures of several types VHDA 1.25disordered Non- crystalline II 1.17 ordered Rhombohedral One C₃ 3.66 III1.14 disordered Tetragonal One C₄ 117 protons can be partially orderedIV 1.27 disordered Rhombohedral One C₃ metastable in ice V phase space V1.23 disordered Monoclinic One C₂ 144 protons can be partially orderedVI 1.31 disordered Tetragonal One C₄ 193 protons can be partly orderedVII 1.50 disordered Cubic four C₃ 150 two interpenetrating ice Icframeworks VIII 1.46 ordered Tetragonal One C₄ 4 low temperature form ofice VII IX 1.16 ordered Tetragonal One C₄ 3.74 low temperature form ofice III, metastable in ice II space X 2.51 symmetric Cubic four C₃symmetric proton form of ice VII XI 0.92 ordered Orthorhombic there C₂low temperature form of ice Ih XI >2.51 symmetric Hexagonal distortedFound in close packed simulations only XII 1.29 disordered TetragonalOne C₄ metastable in ice V phase space XIII 1.23 ordered Monoclinic OneC₂ ordered form of ice V phase XIV 1.29 mostly Orthorhombic One C₄ordered form of ordered ice XII phase XV 1.31 (?) ordered ? ? orderedform of ice VI phase

Cooling liquid hydrogen oxide below its standard freezing pointtypically results in the formation of frozen hexagonal ice. However, ifthe hydrogen oxide is pure and cooled slowly, the liquid hydrogen oxidecan be supercooled to approximately −42° C. Amorphous solids hardenwithout crystallizing, such that if hydrogen oxide is cooled rapidly itresults in formation of a glass-like state, for example, hyperquenchedglassy water. (See e.g., Debenedetti, J. Phys. Condens. Matter, vol. 15,pp. R1669-R1726 (2003), and as cited by Chaplin, worldwideweb atlsbu.ac.uk/water; each of which is incorporated herein by reference.)Generally, hyperquenched glassy water is formed by rapidly spraying afine mist of micrometer-sized hydrogen oxide droplets into very coldliquefied gas, such as propane. Alternatively, a fine mist of hydrogenoxide can be sprayed onto a very cold frozen cell or tissue, forexample, at or below approximately −193° C. Hyperquenched glassy watermay also be formed by cooling capillary tubes containing bulk liquidwater (˜100 μm diameter) with liquid helium, for example, atapproximately −269° C.

As shown in FIGS. 1-4, hydrogen oxide attains various structures andphases depending upon the temperature or pressure of the environment. Asindicated in FIG. 1, for example, hydrogen oxide ice Ic is derived fromhigh density amorphous water or deeply supercooled liquid water, whenput under low temperature or higher pressure. Likewise, as indicated inFIG. 2, the hydrogen oxide has a greater density as a liquid than as asolid under ambient conditions (ice Ih). However, at increasingpressure, at least ice stages III, V, VI, and VII exhibit a greaterdensity than liquid hydrogen oxide. FIG. 3 indicates the phase diagramfor hydrogen oxide based on pressure and temperature variance, whileFIG. 4 shows the specific sub-categories of hydrogen oxide based onphysical properties, such as structure and density, among others, as thetemperature and pressure vary.

Similarly, amorphous solid water is formed from the slow deposition ofhydrogen oxide vapor on a cold metal crystal surface (for example, atless than approximately 2 nm/s), below the temperature of approximately−153° C. Amorphous solid water is a viscous semi-solid material that hasa density of approximately 0.94 g/cm³ and harbors gaps and spaces in itsstructure, as well as reactive hydrogen bonds. These structures areremoved by annealing under vacuum pressure, which allows the material toconvert to a high density glassy water or low density amorphous ice,depending on the temperature. Typically, high density glassy water,which has a density of approximately 1.1 g/cm³, is formed by vapordeposition at approximately −263° C.

Low-density amorphous (LDA) ice also occurs from heating high-densityamorphous (HDA) ice to just above approximately −153° C. at atmosphericpressure, and transforms to cubic ice at approximately −113° C. to −123°C. Low-density amorphous ice is also prepared by submitting low-pressurephases (Ih, Ic, XI, etc.) to high pressure (e.g., approximately 1.0 GPa)at low temperatures (e.g., below approximately −148° C.).

Very-high density amorphous (VHDA) ice is a viscous water state with adensity of approximately 1.25 g/cm³, and is prepared by heatinghigh-density amorphous ice to just above approximately −113° C. andapproximate pressure of 1.15 GPa. When very-high density amorphous iceis heated at different pressures between, e.g., 0.3 and 2 GPa, itre-crystallizes into only the proton disordered ices III, IV, V, XII, VIand VII in order of increasing pressure, but does not typicallyre-crystallize into the proton ordered phases (e.g., ice II).

Typically, the density of liquid water increases with increasedpressure. When liquid water approaches the critical point in theliquid-vapor phase, water enters a supercritical phase where it existsas small but liquid-like hydrogen-bonded clusters dispersed within agas-like phase and its physical properties vary according to changingdensity. Supercritical water is an excellent solvent for non-polarmolecules, due to its low dielectric constant and poor hydrogen bonding.Due to these same properties, supercritical water is typically not agood solvent for electrolytes, which tend to form ionic bonds.

As indicated in FIG. 2, hexagonal ice is less dense than liquid water,whereas the other ice phases are all denser and phase changes occur nearthe liquid and solid densities (See e.g., Loerting et al., J. Phys.:Condens. Matter vol. 18, R919-R977 (2006), which is incorporated hereinby reference). Liquid water density varies with change in temperature orpressure, whereas the density of amorphous ice varies only with changein pressure, but not temperature.

Hydrogen oxide has a high heat of vaporization (approximately 40.7kJ/mol), and a high heat of sublimation (approximately 51.059 kJ/mol at0° C.), which allows for the frozen particle compositions to remainintact for a short time period during which the particles are deliveredto one or more cells or tissues. These properties further enable thefrozen particle compositions to serve as particles for delivery of atleast one therapeutic composition to one or more cells or tissues.

Frozen particle compositions may include a “solid,” such as true solids,semi-solids, and viscous fluid, such as gels, hydrogels, or sols. Frozenparticle compositions including one or more frozen particles may includeparticles that are at least partially frozen, or are entirely frozen.Frozen particle compositions including one or more frozen particles mayinclude one or more subset groups of one or more particles, some ofwhich are entirely frozen and some of which are at least partiallyfrozen. Such frozen particle compositions may include multiple differentconstitutions, wherein a group of frozen particle compositions includesat least one subset of multiple frozen particles, wherein each frozenparticle has an individual therapeutic agent, adhesive agent, biologicalremodeling agent, abrasive, explosive material, reinforcement agent,other agent, a common constitution, or unique constitution. The group offrozen particle compositions may also include at least one subset ofmultiple frozen particles, wherein each frozen particle includesmultiple agents.

A particular plurality of frozen particle compositions may includemultiple frozen particles where various multiple agents are associatedwith a single particle. Likewise, a particular plurality of frozenparticle compositions may include various multiple agents, where eachindividual agent is associated with a single frozen particle. In oneembodiment, a plurality of frozen particle compositions includes anynumber of subsets of frozen particles associated with a particularagent, or other constituent. During the course of any particular methoddescribed herein, one or more plurality of frozen particle compositions,or any particular subset thereof, can be administered in a singletreatment or in multiple treatments. A frozen particle compositionincluding at least one therapeutic agent may be referred to as a“therapeutic composition” or “frozen particle therapeutic composition”herein.

In certain instances, the one or more frozen particle compositions areutilized at a very low temperature, which may increase the degree ofpenetration of the one or more particles or the one or more compositionsfor a biological tissue. In certain instances, the one or more frozenparticle compositions are utilized at higher temperatures, depending onthe freezing temperature of the constituents of the one or moreparticles, the goals of administration or treatment, or other factors.For example, the freezing point of nitrogen is approximately −210° C.,whereas the freezing point of dimethyl sulfoxide (DMSO) is approximately18.45° C.

Hydrogen oxide becomes more viscous as the temperature is decreased tobelow approximately 33° C., or the pressure is increased. Ice Ic isgenerally formed by condensation of water vapor, at ambient pressure andlow temperatures (less than approximately −80° C.), or belowapproximately −38° C. as a mist. (See e.g., Murray et al., Phys. Chem.Chem. Phys. Vol. 8, pp. 186-192 (2006), which is incorporated herein byreference). Ice Ic is also prepared by reducing the pressure onhigh-pressure hydrogen oxide ice at approximately −196° C. It can be thepreferred phase for ice formed from hydrogen oxide droplets smaller thanabout 15 nm in radius, particularly at low temperatures (e.g., −113° C.to −53° C.). (See e.g., Johari, J. Chem. Phys. vol. 122 pp. 194504(2005); Zhang, et al., Chem. Phys. Lett. vol. 421, pp. 251-255 (2006),each of which is incorporated herein by reference).

Ice Ih constitutes a large portion of naturally-occurring snow and ice.Since hexagonal ice exhibits changes in the hydrogen bonding, ice Ihshows anomalous reduction in thermal conductivity with increasingpressure (as does cubic ice and low-density amorphous ice). (See e.g.,Andersson et al., Phys. Rev. B vol. 65 pp. 140201.1-14201.4 (2002),which is incorporated herein by reference).

Ice II maintains a general rhombohedral unit shape, similar to ice I.The density of ice II is approximately 1.17 g/cm³. Ice III maintains ageneral tetragonal unit shape, with a density of approximately 1.14g/cm³. Ice VI also maintains a general tetragonal unit shape, with adensity of approximately 1.31 g/cm³. Ice VII is primarily composed ofmultiple intercalating ice Ic lattices, and has a density ofapproximately 1.66 g/cm³.

Examples of materials that are included in one or more compositionsdescribed herein include, but are not limited to, liquid nitrogen, whichis nontoxic and inert, with a freezing point at 1 atm pressure ofapproximately −210° C. Liquid helium is nontoxic and inert, with afreezing point at 367 psi of approximately −272.2° C. Liquid argon isnontoxic and inert with a freezing point at 1 atm pressure ofapproximately −189.4° C. Liquid neon has a freezing point ofapproximately −245.95° C., while liquid xenon has a freezing point ofapproximately −111.9° C. The freezing point of liquid dimethyl sulfoxide(DMSO) is approximately 18.45° C., and water or other co-solvents candecrease the freezing point. The freezing point of lactated Ringer'ssolution is approximately −45° C. These and other materials can beutilized as described herein either alone, or in combination with othermaterials.

In one embodiment, the frozen particle composition includes a clathrate.Clathrate ice forms from water or other liquids, and contains smallamounts of non-polar molecules (generally gases) under moderate pressureof a few MPa, and temperatures close to 0° C. Clathrate structures canvary, but generally allow a minimum amount of small molecules to fitinto and stabilize gaps without forming covalent or hydrogen bonds withthe hydrogen oxide molecules. Certain clathrates are formed at theinterface of the liquid phase, under atmospheric pressure. Clathratesinclude but are not limited to the structural forms of sI, sII, and sh.In certain instances, noble gases can be used to form clathratecompounds with hydrogen oxide or other molecules. Noble gases generallyhave low polarizability, and tend to be spherically symmetrical, whichallows for solubility with the hydrogen oxide cage. In addition, thesolubility of the noble gases increases considerably as the temperatureis lowered.

The solubility properties of particular noble gases as clathrates withhydrogen oxide are shown in Table IV. (See e.g., Dec et al., J. SolutionChem. vol. 14, pp. 417-429 (1985); Ivanov, et al., J. Struct. Chem. vol.46, pp. 253-263 (2005); Fernandez-Prini, et al., Elsvier, pp. 73-98(2004); Ivanov, et al., Russian J. Gen. Chem. vol. 75, pp. 1851-1856(2005), each of which is incorporated herein by reference.)

TABLE IV Solubility Properties of the Noble Gases Property He Ne Ar KrXe Rn Atomic number 2 10 18 36 54 86 Atomic radius, Å 1.08 1.21 1.641.78 1.96 2.11 ΔG° of solution in H₂O at 25° C., kJ/mol 29.41 29.0326.25 24.80 23.42 ΔH° of solution in H₂O at 25° C., kJ/mol −0.59 −3.80−11.98 −15.29 −18.99 ΔS° of solution in H₂O at 25° C., J/molK −100.6−110.1 −128.2 −134.5 −142.2 Solubility, mM, 5° C., 101,325 Pa H₂O 0.410.53 2.11 4.20 8.21 18.83 D₂O 0.49 0.61 2.38 4.61 8.91 20.41 Solubilityminima, ° C. H₂O 30 50 90 108 110 D₂O 53 53 98 108 116

In one embodiment, the frozen particle composition is substantially inthe form of a microneedle, microscalpel, or other tool. In oneembodiment, the frozen particle composition includes means for piercing,stitching, extracting material, or administering at least one agent to asubstrate.

Cavitized or Compartmentalized Frozen Particle Compositions

In one embodiment, the frozen particle composition includes at least onefrozen particle defining at least one cavity or compartment configuredfor holding at least one agent. In one embodiment, the frozen particleincludes at least one inlet port in fluid communication with the atleast one cavity. In one embodiment, the frozen particle includes atleast one status indicator. In one embodiment, the at least one statusindicator indicates one or more of: content of the at least one cavity,amount of cavity space occupied, or amount of cavity space available. Inone embodiment, the at least one status indicator includes at least oneof a sensor, a magnet, a colorimetric substance, or a physical measuringdevice. In one embodiment, the at least one status indicator measuresone or more of a change in cavity volume, a change in cavity shape, achange in cavity temperature, a change in cavity pressure, a change incavity pH, a change in frozen particle density, a change in frozenparticle volume, a change in frozen particle weight, a change in frozenparticle temperature, a change in frozen particle shape, a change inelectrical field, a change in vehicle magnetic field, a change in frozenparticle pH, a change in the state of an activatable agent of thecomposition, or a change in the state of an activating factor orinactivating factor of the composition.

In one embodiment, the at least one cavity includes at least one of apermeable, semi-permeable or impermeable partition. In one embodiment,the at least one cavity includes at least one of at least one means forat least partially sealing the cavity. In one embodiment, the at leastone cavity includes at least one cap, seal, screw, door, or hinge. Inone embodiment, the at least one cavity is substantially in the form ofat least one of a space-filling curve, a depression, a cylinder, aspheroid, a cuboid, a high aspect ratio shape, a tetrahedron, a pyramid,a channel, or a cone.

In one embodiment, the at least one cavity differs in physical orchemical composition from at least one other cavity of the frozenparticle. In one embodiment, the frozen particle composition includingat least one frozen particle defining at least one cavity or compartmentfurther comprises at least one agent located in the at least one cavityor compartment.

In one embodiment, the cavity or compartment is configured to physicallyor chemically separate the at least one agent from at least one othercavity of the frozen particle. In one embodiment, the at least onecavity or compartment is configured to physically or chemically separatefrom at least one other cavity or compartment of the frozen particleduring administration. In one embodiment the frozen particle compositionincludes at least one agent, and the at least one agent includes atleast one agent in a different phase state than the frozen particle. Inone embodiment, the at least one cavity or compartment includes at leastone of a solid, liquid, or gas. In one embodiment, the at least onecavity or compartment includes at least one of a liquid or gas, and atleast one other cavity or compartment includes a solid.

In one embodiment, the at least one cavity or compartment includes atleast one clathrate. In one embodiment, the at least one cavity orcompartment includes at least one matrix. In one embodiment, the atleast one cavity or compartment is an inner core cavity of at least onefrozen particle. In one embodiment, the at least one cavity orcompartment includes an inner core region and wherein the at least oneagent is at least one of a liquid or gas. In one embodiment, the atleast one cavity or compartment is intercalated with at least one othercavity or compartment.

In one embodiment, the at least one cavity or compartment has a higherconcentration of the at least one agent than any other cavity orcompartment. In one embodiment, the at least one cavity or compartmentincludes a graduated concentration of the at least one agent. In oneembodiment, the at least one cavity or compartment includes varyinglevels of the at least one agent. In one embodiment, the at least oneagent is fractionated. In one embodiment, the cavity or compartmentincludes one or more layers of at least one agent. In one embodiment,the cavity or compartment includes one or more layers of multipleagents. In one embodiment, the at least one agent includes one or moreof a pro-drug or precursor compound. In one embodiment, the at least oneagent includes one or more time-release or extended-releaseformulations. In one embodiment, the at least one agent includes anactivatable agent. In one embodiment, the at least one agent isconfigured to activate upon administration of the frozen particlecomposition. In one embodiment, the at least one activatable agent isconfigured to activate by one or more of an enzymatic reaction, areduction reaction, an oxidation reaction, a reduction-oxidationreaction, a hydrolysis reaction, a dehydration synthesis reaction, aglycosylation reaction, a phosphorylation reaction, a dehydrationreaction, a hydration reaction, a decarboxylation reaction, acondensation reaction, a polymerization reaction, a glycolysis reaction,a gluconeogenesis reaction, a fermentation reaction, a photo chemicalreaction, a thermal reaction, a magnetic reaction, an electricalreaction, an electrochemical reaction, a photolysis reaction, aphotosynthetic reaction, an esterification reaction, altering thepressure on at least one frozen particle composition, altering thecontent of at least one frozen particle composition, altering at leastone chemical property of at least one frozen particle composition,altering at least one physical property of at least one frozen particlecomposition, or applying at least one external stimulus to at least onefrozen particle composition.

In one embodiment, the at least one external stimulus includes one ormore of light, heat, electrical field, magnetic field, orelectromagnetic energy. In one embodiment, the frozen particlecomposition further comprises at least one activating factor or at leastone inactivating factor capable of modulating the activity of the atleast one agent. In one embodiment, the at least one activating factoror the at least one inactivating factor forms at least part of one ormore of a lipid conjugate, carbohydrate conjugate, peptide conjugate,polymer-lipid conjugate, fusion protein, antibody or antibody fragment,receptor or receptor fragment, reversible inhibitor, irreversibleinhibitor, enzyme, gene repressor, gene suppressor, microRNA, siRNA,kinase, gene activator, DNA-binding protein, polymerase, gene promoter,gene enhancer, diamagnetic chemical, explosive material, reactive metal,adhesive agent, abrasive, reinforcement agent, biological remodelingagent, or therapeutic agent.

In one embodiment, the at least one activating or inactivating agent isconfigured to activate by one or more of altering the temperature of atleast one frozen particle composition, altering the pressure on at leastone frozen particle composition, altering the content of at least onefrozen particle composition, altering at least one electrical propertyof at least one frozen particle composition, altering at least onemagnetic property of at least one frozen particle composition, alteringat least one chemical property of at least one frozen particlecomposition, altering at least one physical property of at least onefrozen particle composition, or applying at least one external stimulusto at least one frozen particle composition.

In one embodiment, the at least one cavity or compartment is insubstantially in the form of at least one of an organic or inorganicsmall molecule, clathrate or caged compound, protocell, coacervate,microsphere, Janus particle, proteinoid, laminate, helical rod,liposome, macroscopic tube, niosome, sphingosome, toroid, vesiculartube, vesicle, small unilamellar vesicle, large unilamellar vesicle,large multilamellar vesicle, multivesicular vesicle, lipid layer, lipidbilayer, micelle, organelle, cell, membrane, nucleic acid, peptide,polypeptide, protein, oligosaccharide, polysaccharide, glycopeptide,glycolipid, sphingolipid, glycosphingolipid, glycoprotein,peptidoglycan, lipid, carbohydrate, metalloprotein, proteoglycan,chromosome, cell nucleus, acid, base, buffer, protic solvent, aproticsolvent, nitric oxide, nitric oxide synthase, nitrous oxide, amino acid,micelle, polymer, copolymer, cell receptor, adhesion molecule, cytokine,chemokine, immunoglobulin, antibody, antigen, platelet, extracellularmatrix, blood, plasma, cell ligand, zwitterionic material, cationicmaterial, oligonucleotide, nanotube, or piloxymer.

Agents

In one embodiment, the frozen particle composition includes at least oneagent. In one embodiment, the frozen particle provides a vehicle for theat least one agent. In one embodiment, the frozen particle isconstituted solely by the at least one agent. In one embodiment, theagent includes at least one nontoxic, biocompatible, bioresorbable, orbiodegradable agent. In one embodiment, the one or more agents aremanufactured into a plate or spheroid. In certain instances, the one ormore reinforcement agents, one or more explosive materials, one or moreabrasives, one or more adhesive agents, or one or more therapeuticagents, or one or more biological remodeling agents are utilized in theform of a resin, powder, solution, flake, sheet, film, ribbon, gel,ball, pellet, or bead. (See e.g., U.S. Pat. No. 5,534,584; U.S. Pat. No.5,331,046; each of which is incorporated herein by reference). The oneor more materials or agents of the frozen particle compositions can bein the form of a solid, liquid, or gas. In one embodiment, one or moreof the agents are the same agent. For example, in one embodiment, thefrozen particle composition includes at least one therapeutic agent thatis the same as a reinforcement agent, an adhesive agent, an abrasive, anexplosive material, or a biological remodeling agent. In one embodiment,any one single agent is the same as any single other agent (ie theconstitution of an agent may be the same as another agent, or thefunction of an agent may be the same as another agent).

In one embodiment, the at least one therapeutic agent and the at leastone adhesive agent, biological remodeling agent, abrasive, reinforcementagent, or explosive material are the same agent. In one embodiment, theat least one adhesive agent and the at least one biological remodelingagent, therapeutic agent, abrasive, reinforcement agent, or explosivematerial are the same. In one embodiment, the at least one biologicalremodeling agent and the at least one adhesive agent, therapeutic agent,abrasive, reinforcement agent, or explosive material are the same agent.In one embodiment, the at least one reinforcement agent and the at leastone adhesive agent, therapeutic agent, biological remodeling agent,abrasive, or explosive material are the same. In one embodiment, the atleast one abrasive and the at least one adhesive agent, therapeuticagent, biological remodeling agent, explosive material, or reinforcementagent are the same. In one embodiment, the at least one explosivematerial and abrasive, adhesive agent, therapeutic agent, biologicalremodeling agent, or explosive material are the same.

In one embodiment, the at least one is included as part of at least onecarrier that assists in synthesis or activation of the at least oneagent. In one embodiment, the at least one carrier encompasses the atleast one agent. In one embodiment, the carrier includes a microbe,other cell (such as a cell from a subject or related to a particularsubject, including but not limited to a transgenic cell). In oneembodiment, the cellular carrier is included in the one or more frozenparticle compositions described. In one embodiment, the carrier includesor is substantially in the form of at least one of at least one of anorganic or inorganic small molecule, clathrate or caged compound,protocell, coacervate, microsphere, Janus particle, proteinoid,laminate, helical rod, liposome, macroscopic tube, niosome, sphingosome,toroid, vesicular tube, vesicle, small unilamellar vesicle, largeunilamellar vesicle, large multilamellar vesicle, multivesicularvesicle, lipid layer, lipid bilayer, micelle, organelle, cell, membrane,nucleic acid, peptide, polypeptide, protein, glycopeptide, glycolipid,sphingolipid, glycosphingolipid, glycoprotein, peptidoglycan, lipid,carbohydrate, metalloprotein, proteoglycan, chromosome, nucleus, acid,base, buffer, protic solvent, aprotic solvent, nitric oxide, nitrousoxide, nitric oxide synthase, amino acid, micelle, polymer, copolymer,monomer, prepolymer, cell receptor, adhesion molecule, cytokine,chemokine, immunoglobulin, antibody, antigen, platelet, extracellularmatrix, blood, plasma, cell ligand, zwitterionic material, cationicmaterial, oligonucleotide, nanotube, or piloxymer.

In one embodiment, the at least one agent is frozen. In one embodiment,the at least one agent is at least partially frozen. In at least oneembodiment, the frozen particle composition includes one or more frozenparticles and at least one agent that is not frozen. In one embodiment,the at least one agent includes two or more components configured tocombine upon administration of the at least one agent.

In one embodiment, the at least one agent includes one or more inactivecomponents. In one embodiment, the at least one agent includes two ormore components that are configured to activate when combined. In oneembodiment, the at least one agent includes one or more components thatare configured to activate when administered. In one embodiment, atleast two of the one or more components are included in the same ordifferent frozen particle composition. In one embodiment, at least twoof the one or more components each reside in a separate cavity of thesame or a different frozen particle composition. In one embodiment, atleast one agent is included as a precursor molecule.

In one embodiment, at least one agent is configured to be activatedprior to or subsequent to administration. In one embodiment, at leastone agent is configured to be activated after a prolonged timesubsequent to administration. For example, in cases where the agent isencased or associated with a polymer or other agent that may insulateone or more reactant or retard the explosive or decomposition process,the release of the agent can be delayed. In one embodiment, the frozenparticle composition includes at least one activatable agent. In oneembodiment, the frozen particle composition includes at least oneactivating agent or at least one inactivating agent, or both. In oneembodiment, the at least one agent includes two or more components thatare configured to fuse upon deposition.

In one embodiment, the one or more frozen particle compositionsincluding at least one agent are part of a kit for administration,optionally to at least one substrate (including at least one biologicalcell or tissue). In one embodiment, one or more subsets of frozenparticle compositions include different agents or different componentsof an agent and are administered in a kit or device wherein one subsetis kept separate from another subset until administration of the frozenparticle compositions.

Reinforcement Agents

In one embodiment disclosed herein, one or more reinforcement agents areincluded in the frozen particle composition. Examples of somereinforcement agents include, but are not limited to, polyaramid,vinylester matrix, metal (including but not limited to gold, silver,copper, zinc, brass, tin, bronze, gallium, sodium, potassium, tungsten,steel, iron, carbon, aluminum, copper, platinum, tantalum, rhodium, oralloys thereof), ceramic, fiberglass, cellulose, broad carbide, aromaticpolyamide, nylon, silk, rayon, acetate, modacrylic, olefin, acrylicpolymer or copolymer, acrylamide polymer or copolymer, polyester,aromatic polyester, poly-lactic acid, vinyon, saran, spandex, vinalon,aromatic nylon, vinylidene chloride, modal, polybenzimidazole, sulfur,lyocell, orlon, zylon, high-performance polyethylene,polypyridobenzimidazole, vectran, acrylonitrile rubber, glass, copper,iron, steel, sodium, potassium, calcium, zinc, manganese, carbon,magnesium, alluvium, sand, sugar, calcite, emery, diamond, novaculite,pumice, rouge, borazon, corundum, zirconia alumina, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter. In one embodiment, plant matter may include vegetable matter,nuts or nut products or pieces (e.g., almonds), grains (e.g., oatmeal),wood (e.g., wood fibers) or other stalk material, leaf matter, fruitmatter (including pits or seeds or parts thereof), and other plantmaterial.

In one embodiment, one or more reinforcement agents are made by spinninginto a fiber, wire, or filament. Some non-limiting examples ofreinforcement fibers can be found at, for example, U.S. Pat. No.5,855,663; U.S. Pat. No. 5,652,058; KEVLAR® technical guide, PolymerBulletin, vol. 16, pp. 167-174 (1986), and WO/2003/060002, each of whichis incorporated herein by reference.

The one or more agents are positioned on or in the one or more frozenparticle compositions depending on a given context. For example, thepositioning of one or more agents may consider the particular goal ofadministering the one or more frozen particle compositions, thecomponents of the at least one frozen particle composition, or the needsor desires of a particular outcome of treatment or administration of theone or more frozen particle compositions. In one embodiment, the one ormore agents are located at least on the surface or beneath the surfaceof the one or more frozen particle compositions. In one embodiment, theone or more agents are located within the one or more frozen particlecompositions.

As shown in FIGS. 5 and 6, the strength of hydrogen oxide ice samplesincreases when particular reinforcement agents are added, as published.As indicated in FIG. 5, ice samples exhibit increased strength, asmeasured by beam deflection as an angle of shear when reinforced withfiberglass or kaolin. As indicated in FIG. 6, the maximum stress (inMPa) and strain rate increases when particular reinforcement agents areadded to the hydrogen oxide ice samples.

Abrasives

In certain instances, the frozen particle composition described hereinincludes one or more abrasives. The one or more abrasives may includetreated or untreated abrasives, coated abrasives, bonded abrasives,powders, aggregates, composites, or other forms. In one embodiment, theone or more abrasives include, but are not limited to, polyaramid,vinylester matrix, metal, ceramic, fiberglass, cellulose, broad carbide,aromatic polyamide, nylon, silk, rayon, acetate, modacrylic, olefin,acrylic polymer or copolymer, acrylamide polymer or copolymer,polyester, aromatic polyester, poly-lactic acid, vinyon, saran, spandex,vinalon, aromatic nylon, vinylidene chloride, modal, polybenzimidazole,sulfur, lyocell, orlon, zylon, high-performance polyethylene,polypyridobenzimidazole, vectran, acrylonitrile rubber, glass, copper,iron, steel, sodium, potassium, calcium, zinc, manganese, carbon,magnesium, alluvium, sand, sugar, calcite, emery, diamond, novaculite,pumice, rouge, borazon, corundum, zirconia alumina, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter. In one embodiment, plant matter may include vegetable matter,nuts or nut products or pieces (e.g., almonds), grains (e.g., oatmeal),wood (e.g., wood fibers) or other stalk material, leaf matter, fruitmatter (including pits or seeds or parts thereof), or other plantmaterial.

Explosive Materials

In one embodiment, one or more frozen particle compositions include oneor more explosive materials. Explosive materials are typicallychemically or energetically unstable or produce a sudden expansion ofthe material with a change in pressure. Such a sudden expansion of thematerial under pressure changes is generally accompanied by theproduction of heat. Explosive materials are generally differentiatedaccording to their decomposition rates. Generally, a chemicaldecomposition rate of an explosive material takes years, days, hours,minutes, seconds, or a fraction of a second. Certain explosive materialsare relatively stable, and may maintain their explosive ability for someamount of time. Other explosive materials have relatively high rates ofdecomposition and detonate rapidly.

In one embodiment, frozen particle compositions include one or moreexplosive materials that may include, for example, at least one of ahigh explosive or a low explosive. In one embodiment, the one or moreexplosive materials include at least one of carbonate, carbon dioxide,nitroglycerine, acid, base, epoxy, acrylic polymer or copolymer,acrlyamide polymer or copolymer, urethane, hypoxyapatite, or a reactivemetal. In certain instances, the one or more explosive properties arethe result of activation of one or more explosive materials.

In certain instances, the one or more explosive properties are theresult of inherent tendencies of the frozen particle compositionsthemselves. In certain instances, the one or more explosive propertiesrelate to an external event or stimulus, such as a change in temperatureor pressure. In certain instances, the one or more explosive propertiesrelate to a change in light intensity. In certain instances, the one ormore explosive properties relate to a change in the composition uponadministration or contact with at least one composition, cell, tissue,or subject. In certain instances, the one or more explosive propertiesresult from a temperature or pressure increase relating to penetrationof at least one cell, tissue, or subject. In certain instances, the oneor more explosive properties result from contact with water or othermoisture in a cell or tissue. In certain instances, the one or moreexplosive properties result from contact with at least one substrate. Inaddition to the intensity of the one or more explosives, the one or moreexplosive materials may differ with regard to the volatility, density,toxicity, hygroscopicity, or brisance of a particular explosivematerial.

Explosive materials may contain at least one oxidizer that provides fuelfor certain explosive materials. In certain instances, the oxidizer canbe an oxidizing element, such as oxygen. In certain instances, theoxidizer reacts with a reactive metal; an example of such a compoundincludes reacting fine metal powder (e.g., aluminum or magnesium) withan oxidizer (e.g., potassium chlorate or perchlorate). Chemically purecompounds may have high decomposition rates and lead to an explosion,including but not limited to nitroglycerin, acetone peroxide,trinitrotoluene, nitrocellulose, carbon, carbon monoxide, chlorine,potassium nitrate, sulfur, nitrogen compounds (such as nitrite, nitrate,and azide), potassium chlorate and potassium nitrate, hydrogen, ammoniumnitrate, phosphorous, dinitrogen tetroxide, or others. In oneembodiment, one or more mixtures of organic materials and oxidizers areincluded. In one embodiment, one or more mixtures of reactive metals andoxidizers or oils are included.

In one embodiment, the one or more explosive materials include carbondioxide gas. In one embodiment, carbon dioxide gas is entrapped in thefrozen particle composition. One method of incorporating carbon dioxidegas into at least one frozen particle composition includes liquefyingthe frozen particle composition and introducing carbon dioxide gas whilemaintaining the mixture under pressure. (See e.g., U.S. Pat. Nos.4,289,794; 4,289,790; 4,262,029; 5,439,698, each of which isincorporated herein by reference). The carbon dioxide may also bepresent as a clathrate compound.

In one embodiment, at least one gasified frozen particle is formed, forexample, by contacting fluid with gas under high pressure for asufficient time period to form a gas hydrate. This gas hydrate is thencooled to a lower temperature in order to freeze the remaining unreactedfluid and entrap the gas hydrate. As one non-limiting example, aqueousliquid and carbon dioxide are kept in contact at approximately 0° C. fora time sufficient under a pressure range including at leastapproximately 200 psig to approximately 600 psig, while permittingabsorption in the liquid of the gas in bound form and formation of thegasified ice. This process yields approximately 25-27.5 milliliters ofgas per gram of ice. (See e.g., U.S. Pat. Nos. 4,487,023; 2,975,603;3,086,370; 3,217,503, and 4,404,807, each of which is incorporatedherein by reference).

Similarly, as described in U.S. Pat. No. 2,975,603, which isincorporated herein by reference, water contacted with carbon dioxide ata pressure of approximately 400 psig, in a temperature bath ofapproximately 0° C., is subsequently placed at −10° C. for 24 hours toeffect degasification. As described in U.S. Pat. No. 2,975,603, theresulting product yields approximately 75 volumes of carbon dioxide pergram of ice. Additionally, as described in U.S. Pat. No. 3,086,370,which is incorporated herein by reference, gasified ice products areproduced in a similar manner that contain other gases, such as nitrousoxide, sulfur-containing gases, chlorine-containing gases, inert gases,or carbon monoxide.

In one embodiment, the one or more explosive materials include at leastone of sodium bicarbonate, citric acid, or both. In one embodiment, theone or more explosive materials include hydrogen peroxide.

In certain instances, the at least one frozen particle composition isconfigured to explodes during or upon administration. In certaininstances, the at least one frozen particle composition is configured toexplode prior to or subsequent to administration. In certain instances,the at least one frozen particle composition explodes after a prolongedtime subsequent to administration or delivery to at least one biologicaltissue, or other substrate. For example, in one embodiment, the one ormore explosive materials are encased or associated with a polymer orother agent that may insulate one or more reactant or retard theexplosive or decomposition process.

Therapeutic Agents

In one embodiment, the at least one frozen particle composition includesat least one therapeutic agent. (See, e.g., The Merck Index, 14^(th) Ed.Merck & Co., Inc., Whitehouse Station, N.J. (2006), which isincorporated herein by reference). Other therapeutic agents that areapproved for use in humans can be utilized as at least one therapeuticagent described herein, and can be found at the U.S. Food and DrugAdministration website on the worldwide web at fda.gov, the informationat which is incorporated herein by reference.

In certain instances, the one or more frozen particles themselvesprovide at least one therapeutic benefit. In certain instances, the oneor more frozen particles act as vehicles for one or more therapeuticagents that provide at least one therapeutic benefit. In one embodiment,the one or more frozen particles including at least one therapeuticagent is inert.

In one embodiment, the at least one therapeutic agent includes at leastone of an anti-tumor agent, antimicrobial agent, anti-viral agent,analgesic, antiseptic, anesthetic, diagnostic agent, anti-inflammatoryagent, vaccine, cell growth inhibitor, cell growth promoter, chemicaldebridement agent, immunogen, antigen, radioactive agent, apoptoticpromoting factor, angiogenic factor, anti-angiogenic factor, hormone,enzymatic factor, enzyme, papain, collagenase, protease, peptidase,elastase, urea, vitamin, mineral, nutraceutical, histatin, honey, alciumalginate, antiogenic factor, hormone, vitamin, mineral, nutraceutical,cytokine, chemokine, probiotic, coagulant, anti-coagulant, phage,prodrug, prebiotic, blood sugar stabilizer, smooth muscle cellactivator, epinephrine, adrenaline, neurotoxin, neuro-muscular toxin,Botulinum toxin type A, microbial cell or component thereof, or virus orcomponent thereof. In one embodiment, the nutraceutical includes one ormore of a flavonoid, antioxidant, beta-carotene, anthocyanin,alpha-linolenic acid, omega-3 fatty acids, yeast, bacteria, algae, othermicroorganisms, plant products, or animal products. In one embodiment,the analgesic or anesthetic includes one or more of any aminoamid oraminoester local anesthetic, ibuprofen, morphine, codeine, aspirin,acetaminophen, lidocaine/lignocaine, ropivacaine, mepivacaine,benzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine/larocaine, propoxycaine, procaine/novocaine, proparacaine,tetracaine/amethocaine, articaine, bupivacaine, carticaine,cinchocaine/dibucaine, etidocaine, levobupivacaine, piperocaine,prilocaine, trimecaine, saxitoxin, or tetrodotoxin.

In one embodiment, the therapeutic agent includes at least oneanti-inflammatory agent, including but not limited to steroids,non-steroidal anti-inflammatory drugs, topical anti-inflammatory agents,or subcutaneously administered non-steroidal anti-inflammatory drugs(e.g. diclofenac).

In one embodiment, the analgesic includes but is not limited to one ormore of paracetamol (acetaminophen), non-steroidal anti-inflammatorydrugs (NSAIDs), salicylates, narcotics, or tramadol. In one embodiment,the analgesic includes but is not limited to aspirin, rofecoxib,celecoxib, morphine, codeine, oxycodone, hydrocodone, diamorphine,pethidine, buprenorphine, amitriptyline, carbamazepine, bagapentin,pregabalin, ibuprofen, naproxen, lidocaine, a psychotropic agent,orphenadrine, cyclobenzaprine, scopolamine, atropine, gabapentin,methadone, ketobemidone, or piritramide.

In one embodiment, the at least one therapeutic agent includes one ormore antiseptic, including but not limited to one or more of an alcohol,a quaternary ammonium compound, boric acid, hydrogen peroxide,chlorhexidine gluconate, iodine, mercurochrome, octenidinedihydrochloride, phenol (carbolic acid) compounds, sodium chloride, orsodium hypochlorite.

In one embodiment, the antiseptic includes but is not limited to one ormore of povidone-iodine, iodine, ethanol, 1-propanol,2-propanol/isopropanol, benzalkonium chloride, cetyl trimethylammoniumbromide, cetylpyridinium chloride, benzethonium chloride, chlorhexidine,octenidine dihydrochloride, or carbolic acid.

In one embodiment, the at least one therapeutic agent is anantimicrobial agent, and includes at least one of an anti-fungal agent,antibiotic agent, anti-bacterial, anti-parasitic agent, or anti-wormagent. In certain instances, the antimicrobial agent may occur innature, or it can be synthetic.

In one embodiment, the at least one therapeutic agent includes one ormore of a penicillin, cephalosporin, polymixin, sulfonamide, beta-lactamantibiotic, beta-lactamase inhibitor, enediynes, lincosamide antibiotic,nitroimidazole antibiotic, pleuromutilin antibiotic, polyketideantibiotic, polymyxin antibiotic, polypeptide antibiotic, antimicrobialpeptides, quinolone antibiotic, rifamycin antibiotic, sulfonamideantibiotic, tetracycline antibiotic, aminoglycoside antibiotic,macrolide, tetracycline, cyclic lipopeptide, glycylcycline, oroxazolidinone. In one embodiment, the at least one therapeutic agentincludes one or more of amoxicillin, tobramycin, levofloxacin,gatifloxacin, moxifloxacin, streptomycin, oxytetracycline,chloramphenicol, or ampicillin.

In one embodiment, the at least one therapeutic agent includes one ormore anti-tumor agent, at least one of which may also be identified as acytotoxic agent, or chemotherapy agent. Non-limiting examples of ananti-tumor agent for use as described herein include at least one of analkylating agent, antimetabolite, anthracycline, plant alkaloid (such aspaclitaxel), topoisomerase inhibitor, monoclonal antibody, or tyrosinekinase inhibitor. In one embodiment, the therapeutic agent includes oneor more of imatinib, mechlorethamine, cyclophosphamide, chlorambucil,azathioprine, mercaptopurine, vinca alkaloid, taxane, vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide,teniposide, amsacrine, dactinomycin, trastuzumab, cetuximab, rituximab,bevacizumab, dexamethasone, finasteride, tamoxifen, goserelin,telomerase inhibitor, dichloroacetate, aminopterin, methotrexate,pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine,pentostatin, thioguanine, cytarabine, decitabine,fluorouracil/capecitabine, floxuridine, gemcitabine, enocitabine,sapacitabine, chloromethine, cyclophosphamide, ifosfamide, melphalan,bendamustine, trofosfamide, uramustine, carmustine, fotemustine,lomustine, nimustine, prednimustine, ranimustine, semustine,spretpozocin, carboplatin, cisplatin, nedaplatin, oxaliplatin, triplatintetranitrate, satraplatin, busulfan, mannosulfan, treosulfan,procarbazine, decarbazine, temozolomide, carboquone, ThioTEPA,triaziquone, triethylenemelamine, docetaxel, larotaxel, ortataxel,tesetaxel, vinflunine, ixabepilone, aclarubicin, daunorubicin,doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin,zorubicin, metoxantrone, pixantrone, actinomycin, bleomycin, mitomycin,plicamycin, hydroxyurea, camptothecin, topotecan, irinotecan, rubitecan,belotecan, altretamine, amsacrine, bexarotene, estramustine, irofulven,trabectedin, cetuximab, panitumumab, trastuzumab, rituximab,tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab,axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib,imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib,sunitinib, vandetanib, alvocidib, seliciclib, aflibercept, denileukindiftitox, aminolevulnic acid, efaproxiral, porfimer sodium, talaporfin,temoporfin, verteporfin, alitretinoin, tretinoin, anagrelide, arsenictrioxide, asparaginase/pegaspergase, atrasentan, bortezomib, carmofur,celecoxib, demecolcine, elesclomol, elasamitrucin, etoglucid,lonidamine, lucanthone, masoprocol, mitobronitol, mitoguanzone,mitotane, oblimersen, omacetaxine, sitimagene ceradenovec, tegafur,testolactone, tiazofurine, tipifarnib, or vorinostat.

In one embodiment, at least one nutraceutical is included. At least onenutraceutical includes but is not limited to, one or more of an extractof plant or animal matter (e.g., an oil, aqueous, or solid extract), avitamin, a mineral, a mixture or solution, a food supplement, a foodadditive, a food fortification element, or other nutraceutical. In oneembodiment, at least one nutraceutical includes but is not limited toresveratrol, an antioxidant, psyllium, sulforaphane, isoflavonoid,alpha-linolenic acid, beta-carotene, anthocyanins, phytoestrogens,polyphenols, polyphenons, catechins, benzenediols, tannins,phenylpropanoids, caffeine, alcohol, or others.

In one embodiment, at least one therapeutic agent includes one or morevaccine. In one embodiment, the composition including at least onevaccine includes at least one prophylactic vaccine or therapeuticvaccine. In one embodiment, the at least one therapeutic vaccineincludes at least one anti-cancer vaccine. In one embodiment, the atleast one vaccine includes at least one of an anti-tumor agent,antimicrobial agent, anti-viral agent, immunogen, antigen, live microbe,dead microbe, attenuated microbe, microbe or component thereof, livevirus, recombinant virus, killed virus, attenuated virus, viruscomponent, plasmid DNA, nucleic acid, amino acid, peptide, protein,glycopeptide, proteoglycan, glycoprotein, glycolipid, sphingolipid,glycosphingolipid, cancer cell or component thereof, organic orinorganic small molecule, or toxoid.

One or more vaccine may include but not be limited to, vaccinescontaining killed microorganisms (such as vaccines for flu, cholera,bubonic plague, and hepatitis A), vaccines containing live, attenuatedvirus or other microorganisms (such as vaccines for yellow fever,measles, rubella, and mumps), live vaccine (such as vaccines fortuberculosis), toxoid (such as vaccines for tetanus, diphtheria, andcrotalis atrox), subunit of inactivated or attenuated microorganisms(such as vaccines for HBV, VLP, and HPV), conjugate vaccines (such asvaccines for H influenzae type B), recombinant vector, DNA vaccination.In one embodiment, the at least one vaccine includes but is not limitedto rubella, polio, measles, mumps, chickenpox, typhoid, shingles,hepatitis A, hepatitis B, diphtheria, pertussis, rotavirus, influenza,meningococcal disease, pneumonia, tetanus, rattlesnake venom, virus-likeparticle, or human papillomavirus, or anti-cancer vaccine.

In one embodiment, the at least one therapeutic agent includes at leastone adjuvant. The at least one adjuvant may include but not be limitedto one or more organic or inorganic compounds. The at least one adjuvantmay include but not be limited to at least one of a liposome, virosome,lipid, phospholipid, mineral salt, single-stranded DNA, double-strandedRNA, lipopolysaccharide, molecular antigen cage, CpG motif, microbialcell wall or component thereof, squalene, oil emulsion, surfactant,saponin, isolated microbial toxin, modified microbial toxin, endogenousimmunomodulator, or cytokine. In one embodiment, the at least oneadjuvant and the at least one vaccine are located in at least one of thesame cavities of the same frozen particle composition. In oneembodiment, the at least one adjuvant and the at least one vaccine arelocated in different cavities of the same frozen particle composition.In one embodiment, two or more frozen particle compositions of aplurality of frozen particle compositions include one or more similarvaccines. In one embodiment, two or more frozen particle compositions ofa plurality of frozen particle compositions include one or moredissimilar vaccines.

In one non-limiting example, a composition includes one or more frozenparticles including paclitaxel and at least one other constituentincluding at least one frozen component including air, oxygen, nitrogen,carbon dioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, or argon.

In one non-limiting embodiment, a composition includes one or morefrozen particles including one or more pegylated cytokines or one ormore anti-tumor compounds; wherein the one or more frozen particlesinclude nitrogen, air, oxygen, carbon dioxide, hydrogen oxide, helium,xenon, krypton, chlorine, bromine, methane, or argon.

Adhesive Agents

In one embodiment, at least one adhesive agent is included in one ormore frozen particle compositions. In one embodiment, the at least oneadhesive agent includes at least one monomer, prepolymer, polymer, orcopolymer. In one embodiment, the at least one adhesive agent includesat least one monomer of self-polymerizing agent. In one embodiment, theat least one adhesive agent is configured to polymerize uponadministration to at least one substrate. In one embodiment, the atleast one adhesive agent is configured to polymerize at or above thetemperature of the at least one substrate. In one embodiment, the atleast one adhesive agent is configured to polymerize at or above thetemperature of at least one biological tissue. In one embodiment, the atleast one adhesive agent is configured to polymerize at or above thetemperature of at least one subject.

In one embodiment, the at least one adhesive agent includes one or moreof a cement, glue, paste, fixative, or bonding agent. In one embodiment,the at least one adhesive agent includes one or more of a solid, liquid,or gas.

In one embodiment, the at least one adhesive agent is at least one ofnon-toxic, biocompatible, biodegradable or bioresorbable. In oneembodiment, the at least one adhesive agent resists biodegradation orbioresorption. In one embodiment, the at least one adhesive agent is notbiocompatible, or may induce a response from the at least one biologicaltissue, or subject's body. In one non-limiting example, one or morefrozen particle compositions are administered with or contain at leastone therapeutic agent, such as a vaccine, and optionally, at least oneadhesive agent (which may act as an adjuvant).

In one embodiment, the at least one adhesive agent is degradable orresorbable (e.g., dissolvable sutures constructed from or secured withan adhesive). See e.g., Sierra, and Saltz, “Surgical Adhesives andSealants,” Technomic Pub. Co., 1996, which is incorporated herein byreference. In one embodiment, the at least one adhesive agent stimulatescell or tissue growth, allowing for healing of a wound (e.g., burn,surgery incision, etc.) while the adhesive agent itself subsequentlydegrades, dissolves, or is resorbed by the at least one substrate,including at least one biological tissue or the subject's body. In oneembodiment, the at least one adhesive agent stimulates or increasestissue regeneration. In one embodiment, the at least one adhesive agentsuppresses or decreases scarring or keloid formation or recurrence.

In one embodiment, one or more frozen particle compositions include atleast one liquid adhesive agent. For example, the freezing point ofacrylic or epoxy resins is generally approximately −10° C. to −15° C.,while the freezing point of hydrogen oxide water is approximately 0° C.Thus, in one embodiment, one or more frozen hydrogen oxide particlecompositions include at least one liquid adhesive agent.

In one embodiment, the at least one adhesive agent includes one or moreof a hemostat, such as a mechanical hemostat (including but not limitedto, porcine gelatin, bovine gelatin, oxidized regenerated cellulose, orpolysaccharide spheres), an active hemostat (including but not limitedto, bovine thrombin, human pooled thrombin, or recombinant thrombin), aflowable hemostat (including but not limited to, bovine gelatin andhuman thrombin, or porcine gelatin with or without thrombin), or ahemostat and sealant (such as fibrin sealants of human pooled fibrin;human fibrin; plasma, collagen, and bovine thrombin; animal fibrin orthrombin, or others). In one embodiment, the adhesive agent includes oneor more of a sealant (such as polyethylene glycol (PEG) polymers,including dual PEG or single PEG). In one embodiment, the adhesive agentincludes but is not limited to albumin (such as bovine serum albumin)and glutaraldehyde. (See, for example, Spotnitz and Burks, Transfusion,pp. 1502-1516, Vol. 48, 2008; which is incorporated herein byreference.)

In one embodiment, the at least one adhesive agent includes at least onenaturally-occurring substance, such as gelatin, blood plasma, albumin,collagen, fibrin, fibrinogen (including lytic fragments, for exampleFPA, FPB, fragments D and E), hyaluronate, hyaluronan,glycosaminoglycans, chitin, thrombin, Factor XIII, or other substances.In one embodiment, the at least one adhesive agent includes at least oneartificial or synthetic substance, such as an acrylic polymer orcopolymer, acrylamide polymer or copolymer, polyacrylic acid (includingbut not limited to zinc polycarboxylate, resin bonding, or glass ionomercement), epoxy, urethane, gum arabic, polyester, polyhydroxyalkanoate,poly(L-lactic acid), polyglycolide, polylactic acid, polyether, polyol,polyvinylpyrrolidone, pyroxylin,polymethyacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, polyelectrolyte, maleicpolyelectrolyte, cellulose, resilin, cyanoacrylate, isocyanate,(including but not limited to 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, monomeric n-butyl-2-cyanoacrylate,butyl-2-cyanoacrylate, methyl 2-cyanoacrylate, or its higher homologs(ethyl, butyl, octyl, etc.), or polyisohexylcyanoacrylate), fibrin,thrombin, firbrinogen, hyaluronate, chitin, Factor XIII, Factor XII,silk, nylon, collagen, glycosaminoglycan, selectin, polyurethane,methacrylate, polysulfide, polyanhydride, polydioxanone,poly-p-dioxanone, albumin, glutaraldehyde, polyethylene glycol,hydrogel, soy or other plant based adhesives, or gelatin. In at leastone embodiment, the adhesive agent includes gecko glue. In at least oneembodiment, the adhesive agent includes microscopic seta configured toadhere by van der Waals forces.

In one embodiment, the at least one adhesive agent includes one or moreof a globin, hemoglobin, heme group, carbohydrate, cell or cellcomponent, silicone, hydroxyapatite, acrylic polymer or copolymer,acrylamide polymer or copolymer, hyaluronate or hyaluronic acid,carboxymethylcellulose, healon, polymer or biopolymer,gelatin-resorcinol-formaldehyde (GRF) combination, a fibrin-collagencombination, or a fibrinogen-thrombin combination. In one embodiment,the at least one adhesive agent includes one or morenaturally-occurring, artificial, or synthetic polymers, including butnot limited to urethane prepolymers or polymers, cyano-based polymers,polyether, polyol, polyvinylpyrrolidone, pyroxylin/nitrocellulose,polymethylacrylate-isobutene-monoisopropylmaleate, acrylate polymers orsiloxane polymers (such as acrylate terpolymer,polyphenylmethylsiloxane, hexamethyldisiloxane or isooctane solventbased polymers). (For other specific examples of adhesive agents see,e.g., U.S. Pat. Nos. 4,740,534 and 7,264,823; and U.S. PatentApplication Nos. 20040097990, 20070161109, and 20070031474, each ofwhich is incorporated herein by reference). In one embodiment, the atleast one adhesive agent includes a combination of more than oneadhesive agents.

In one embodiment, the at least one adhesive agent includes at least onecrosslinking or derivatized agent. In one embodiment, the at least oneadhesive agent is configured to form a crosslink bond with at least onecomponent of at least one substrate. In one embodiment the crosslinkbond of the at least one adhesive agent is configured for modulation byone or more of a chemical agent, change in pH, change in exposure toair, vacuum, change in moisture content, change in pressure, or changein temperature. In one embodiment, the formation of a crosslink bond ofthe at least one adhesive agent is configured for modulation by exposureof the at least one adhesive agent to one or more of electromagneticenergy, optical energy, thermal energy, laser energy, ionizingradiation, non-ionizing radiation, or sonic energy.

In one embodiment, one or more constituent of the at least one adhesiveagent includes a crosslinked constituent (such as gelatin or albuminthat is cross-linked with, for example, glutaraldehyde), or aderivatized constituent (such as derivatized collagen). In oneembodiment, the at least one adhesive agent includes one or moreconstituents that are configured to crosslink with one or moresubstances in the at least one biological tissue. The crosslinking bondcan form upon administration of the at least one adhesive agent to theat least one biological tissue, or upon administration of at least oneof a chemical agent (such as an acid, base, enzyme, epoxide, diepoxide,1,4-butanediol diglycidyl ether, glutaraldehyde, polysaccharide, orother chemical agent), air, moisture (such as from a biological fluid),electromagnetic energy (including ultraviolet light), optical energy,thermal energy, laser energy, ionizing radiation, non-ionizingradiation, or sonic energy to the at least one adhesive agent.

In one embodiment, the at least one adhesive agent includes one or moreprotein glue, including but not limited to protein, peptide, or aminoacid-based substances. In one embodiment, the at least one adhesiveagent includes one or more naturally-occurring or synthetic component.In one embodiment, the at least one adhesive agent includes one or morenaturally-occurring or synthetic polyphenolic protein from mussels,wherein the polyphenolic protein is optionally cross-linked by acatechol oxidase. In one embodiment, the at least one adhesive agentincludes mussel adhesive protein. In one embodiment, the mussel adhesiveprotein includes lysine, hydroxylated amino acids, and dopa. In certaininstances, the mussel adhesive protein includes dihydroxyphenylalanine.In one embodiment, the at least one adhesive agent includes prolamine.In one embodiment, the at least one adhesive agent includes one or morechemotactic agent, such as transforming growth factor beta (TGF-β).

In one embodiment, fibrin sealant or fibrin glue can be formed asindicated in the table herein, or from two components: one containingfibrinogen and calcium chloride solution and the other containingthrombin solution and epsilon amino caproic acid (EACA).

In one embodiment, the at least one adhesive agent includes one or morehydrogel. See, for example, U.S. Pat. No. 6,103,528, which isincorporated herein by reference. One non-limiting example of a hydrogelincluded in a composition as described herein includes polyethyleneglycol, polylactic acid, polytrimethylene carbonate, polycarophil,carbopol, polyox, chitosan, polyvinylpyrrolidone, block polymers orblock copolymers, polymethylvinyl ether-maleic anhydride, or otherconstituents. In certain embodiments, the hydrogel may include aconstituent with a polymerizable end cap, such as an acrylate ester. Inone embodiment, the at least one adhesive agent at least partiallygenerates a wound dressing, such as a sheet, bandage, film, or otherpermeable, semi-permeable, or impermeable covering. In one embodiment,the at least one wound dressing at least partially includes natural,synthetic, or artificial skin or skin deposit. (See, for example,Boateng et al., J. Pharm. Sciences. vol. 97, pp. 2892-2923 (2008)).

Some specific non-limiting examples of particular adhesive agents thatare included in at least one composition described herein are listed inTable II herein. (Adapted from Smith, Ch. 7, p. 574, Table 1; Ratner, etal, Biomaterials Science, Second Edition, 2004; Elsevier Acad. Press.,which is incorporated herein by reference).

TABLE II Type of tissue Components Possible setting or bonding reactionCyanoacrylate Butyl or isobutyl Addition polymerization cyanoacrylateFibrin sealant Fibrinogen (with or without Clot formation Factor XIII)Thrombin, CaCl₂ Factor XIII Clot formation GRF glue Gelatin, resorcinol,Condensation formaldehyde (glutaraldehyde or glyoxal can be used inaddition to or instead of formaldehyde) Hydrogel Block copolymers ofPEG, Photoinitiated addition polylactic acid and acrylate polymerizationesters Acrylic bone cement Methyl methacrylate and Pertoxide-amineinitiated polymethyl methacrylate addition polymerization Dental cementsZinc oxide powder, Acid-base reaction, zinc phosphoric acid complexationZinc phosphate Zinc complexation Zinc polycarboxylate Zinc oxide powder,aqueous Acid-base reaction, zinc polyacrylic acid complexation Glassionomer Ca, Sr, Al silicate glass Acid-base reaction, metal(polyalkenoate) powder aqueous ion complexation polyacrylic-itatomicacid or polyacrylic-maleic acid Resin-based Aromatic or urethanePeroxide-amine or dimethacrylate monomers, photoinitiated silicate orother glass fillers polymerization and aqueous polyacrylic acid-photoinitiated addition itaconic acid-methacrylate polymerizationcomonomers Resin-modified glass Hydroxyethyl methacrylate ionomeraromatic or urethane diamethacrylates, Ca, Sr, Al glass powder Dentinadhesive Etchant: phosphoric acid Photoinitiated addition primer:carboxylate or polymerization phosphate Monomers hydroxyethylmethacrylate/water/solvent Bonding agent: urethane or aromaticdimethacrylate monomers

In one embodiment, the at least one adhesive agent is configured toconvert to at least one therapeutic agent upon administration of the atleast one adhesive agent. In one embodiment, the at least one adhesiveagent is configured to undergo one or more of hydration, hydrolysis,hydrogenolysis, condensation, dehydration, or polymerization uponadministration of the at least one adhesive agent. In one embodiment,the at least one adhesive agent includes a methacrylate. In oneembodiment, the at least one adhesive agent includes at least one ofpoly(N,N-dimethyl-N-(ethoxycarbonylmethyl)-N-[2′-(methacryloyloxy)ethyl]-ammoniumbromide) or poly(sulfobetaine methacrylate).

In one embodiment, the at least one adhesive agent is configured to formone or more of a hydrogen bond, ionic bond, covalent bond, ornoncovalent bond with at least one substrate.

In certain instances, at least one adhesive agent is provided to atleast one substrate, including but not limited to at least onebiological tissue, in an inactive form. In certain instances, the atleast one adhesive agent is configured to polymerize or activate duringadministration of the at least one adhesive agent to at least onesubstrate, or shortly thereafter.

In one embodiment, the at least one adhesive agent is compatible withmoist or wet tissues. In one embodiment, the at least one adhesive agentdistributes evenly over the tissue surface. In one embodiment, the atleast one adhesive agent quickly forms a durable bond. In oneembodiment, the bonding time of the at least one adhesive agent iscontrollable. In one embodiment, the bonding time of the at least oneadhesive agent is controlled or regulated. In one embodiment, the atleast one adhesive degrades in a relatively short period of time. In oneembodiment, the at least one adhesive agent is configured to be resorbedby the tissue to which it is applied, or by the subject's body. In oneembodiment, the at least one adhesive agent maintains an appropriateviscosity for the application, provides adequate working time prior tobonding or setting, develops good adhesion, modulates hemostasis,modulates wound healing, reduces fibrosis, or provides at least oneantimicrobial effect. In one embodiment, the at least one compositionincluding at least one adhesive provides a local depot for at least onetherapeutic agent.

In one embodiment, the at least one adhesive agent includes an activesurface (i.e. having a bioglass, calcium phosphate, or biochemicallyactive surface that can stimulate an in vivo response). In oneembodiment, the at least one adhesive agent assists in delivering one ormore therapeutic agents, including but not limited to antibiotics,vaccines, growth factors (e.g., members of the Fibroblast Growth Factor,members of the Bone Morphogenic Protein family, members of theTransforming Growth Factor-beta family, or others), transcriptionfactors, anti-inflammatory agents, pain relievers, hemostatic agents,chemotherapeutic agents (e.g., 5-fluorouracil, paclitaxel, or others),chemokines, cytokines, angiogenic or anti-angiogenic factors, enzymes,stem cells, cellular organelles, or other therapeutic agents describedherein.

In one embodiment, the at least one adhesive agent is delivered as aprecursor molecule that is configured to activate by an additionalactivation step or event. In one embodiment, two or more components areconfigured to combine upon administration of the at least one adhesiveagent. In one embodiment, the combination of the two or more componentsmodifies at least one property of the adhesive agent. In one embodiment,the at least one property includes one or more of initiation of adhesivebond formation, strength of adhesive bond, adhesive bonding time, bondflexibility, bond biodegradability, bond bioresorbability, bondbiocompatibility, or durability of adhesive bond. In one embodiment, theat least one property includes one or more of polymerization of theadhesive agent, or crosslinking of the adhesive agent. In oneembodiment, two or more frozen particle compositions are administered;wherein at least one administration parameter is different for the twoor more frozen particle compositions. In one embodiment, the at leastone administration parameter includes at least one of: constitution ofthe frozen particle composition, formulation of the frozen particlecomposition, size of the frozen particle compositions, shape of thefrozen particle composition, angle of administration of the frozenparticle composition, velocity of administration of the frozen particlecomposition, quantity of frozen particle compositions administered, rateof administration of more than one frozen particle composition, spatiallocation for administration of the frozen particle compositions,temporal location for administration of the frozen particlecompositions, method of administration of the frozen particlecompositions, timing of administration of the frozen particlecompositions, modulation of administration of the frozen particlecompositions, deposition of the frozen particle compositions, or rate ofdeposition of at least one agent included in the frozen particlecompositions.

In one embodiment, the at least one adhesive agent maintains theapproximation of tissue of at least one wound of a subject. In oneembodiment, the at least one adhesive agent forms a bond that resistsseparation between at least two aspects of a substrate. In oneembodiment, the at least one adhesive agent is administered to the atleast one substrate, such as a biological tissue or structure, prior to,during, or subsequent to a surgical procedure. Specific, non-limitingexamples of surgical procedures include thoracic surgery, cardiovascularsurgery, vascular surgery, neurological surgery, plastic surgery oraesthetic surgery, ophthalmic surgery, skin or connective tissuesurgery, or abdominal surgery.

In one embodiment, at least one frozen particle composition includes anadhesive agent which provides a means for the repair, closure,maintenance of approximately the same tissue of a wound, treatment of awound, or joining at least one substrate to another or joining at leastone aspect of a substrate to another aspect of the same or differentsubstrate.

In one embodiment, and as described herein, compositions and methodsrelate to the same or different frozen particle compositions, and areadministered simultaneously, sequentially, randomly, or in anotherorder. In certain instances, the at least one composition isadministered that contains at least one adhesive agent as well as one ormore other agents, such as bonding agents, that include functionalgroups or reactive side chains.

In one non-limiting example, polymerizable dimethacrylate monomers mixedwith composite formulations are administered to calcified tissue, suchas bone or tooth. In another non-limiting example, acid etching orpriming of the cell or tissue surface (such as a calcified surface), isachieved by administration of phosphoric acid or another acidicsubstance. In certain instances, the acidic substance includesfunctional groups, such as polycarboxylate or polyphosphate. Next, oneor more agents can be administered that react with the functionalgroups, such as hydrophilic monomers (including but not limited tohydroxyethyl methacrylate).

In one embodiment, the at least one adhesive agent forms one or more ofa hydrogen bond, ionic bond, covalent bond, or non-covalent bond uponadministration to at least one substrate. In one embodiment the at leastone adhesive agent includes at least one crosslinking or derivatizedagent. In one embodiment, the at least one adhesive agent forms acrosslink bond with at least one component of at least one substrate towhich the adhesive agent is administered. In one embodiment, thecrosslink bond of the at least one adhesive agent is modulated by one ormore of a chemical agent, change in pH, change in exposure to air,vacuum, change in moisture content, change in pressure, or change intemperature. In one embodiment, formation of a crosslink bond of the atleast one adhesive agent is modulated by exposure of the at least oneadhesive agent to one or more of electromagnetic energy, optical energy,thermal energy, laser energy, ionizing radiation, non-ionizingradiation, or sonic energy.

In one embodiment, adhesive agents can be selected for a particular useas described herein, based on factors including, but not limited to,viscosity, adhesive tenacity, kinetic rates of monomer formation,polymerization (with or without covalent cross-linking), ability to becryoprecipitated, tensile strength, ability to restore biomechanicaltissue integrity, in vivo effectiveness, or other factors. In certaininstances, these or other factors can be measured and selection of theone or more particular adhesive agents can be based on thosemeasurements. In certain instances, these or other factors can bemeasured by standard methods, including but not limited to, in vitroanalysis, in vivo experiments (e.g., animal studies), ex vivoexperiments, in planta experiments, or other methods.

In one embodiment, a method for providing at least one agent to at leastone substrate comprises administering at least one frozen particlecomposition to at least one substrate, wherein the at least one frozenparticle composition includes one or more frozen particles as describedherein, and at least one agent.

In one embodiment, a method for providing at least one adhesive agent toat least one substrate comprises administering at least one frozenparticle composition to at least one substrate, wherein the at least onefrozen particle composition includes one or more frozen particles asdescribed herein, and at least one adhesive agent.

In one embodiment, a method of maintaining the approximation of tissueof at least one wound of a subject comprises administering at least onefrozen particle composition to at least one wound of a subject for atime sufficient to maintain the approximation of tissue of the at leastone wound; wherein the at least one frozen particle composition includesone or more frozen particle compositions including at least one agent(such as an adhesive agent, biological remodeling agent, reinforcementagent, therapeutic agent, abrasive, or explosive material) as describedherein.

In one embodiment, the at least one frozen particle composition includesa detectable state that varies with its adhesive state. In oneembodiment, the adhesive agent includes one or more eposy adhesive,acrylic adhesive, urethane adhesive, polyurethane adhesive, siliconeadhesive, cationic adhesive, anerobic adhesive, urethane acrylate,polyester acrylate, methacrylate, methyacrylate, or cyanoacrylate.

In one embodiment, the at least one adhesive agent includes at least oneα-cyanoacrylate and a fluorescent compound including at least one of abis-benzoxazolyl compound, pyrylium salt, quantum dot, or coumarincompound. In one embodiment, the at least one adhesive agent includes anα-cyanoacrylate and 2,5-bis-(5-tert-butyl-2-benzoxasolyl)-thiophene. Inone embodiment, the at least one adhesive agent includes one or more ofa base component, initiator component, or activator component. In oneembodiment, the at least one adhesive agent further includes at leastone curing component. In one embodiment, the at least one adhesive agentincludes at least one photopolymerizable adhesive, photocurableadhesive, thermal curable adhesive, free radical curable adhesive, oraerobic curable adhesive. In one embodiment, the at least one adhesiveagent includes one or more adhesive agent configured to polymerize uponexposure to infrared light, ultraviolet light, x-ray, visible light, orother electromagnetic radiation.

In one embodiment, the adhesive agent includes at least one dyecoinitiator. In one embodiment, the at least one dye coinitiatorincludes at least one of a bis-benzoxazolyl compound, pyrylium salt,QTX, safranine O, fluorescein, eosin yellow, eosin Y, eosin B, ethyleosin, eosin bluish, erythrosine B, erythrosine yellowish blend,toluidine blue, 4′,5′-dibromofluorescein, Rose Bengal B, cyanine,pyronin GY, cresyl violet, brilliant green, lissamine green BN,rhodamine B, methylene blue, crystal violet, phosphine oxide, orcoumarin compound.

Biological Remodeling Agents

In one embodiment, one or more frozen particle compositions include atleast one biological remodeling agent. In one embodiment, the at leastone biological remodeling agent includes one or more extracellularmatrix components. In one embodiment, the at least one biologicalremodeling agent provides at least one chemical or biochemical functionto the at least one biological tissue. In one embodiment, the biologicalremodeling agent promotes growth of at least one biological tissue. Inone embodiment, the at least one biological remodeling agent promotes atleast one of cell migration, cell attachment, cell retention, celldifferentiation, cell proliferation, apoptosis, angiogenesis, diffusionof materials, nucleic acid expression, protein translation, proteinmodification, protein secretion, carbohydrate production, carbohydratesecretion, fat production, or fat secretion.

In one embodiment, the at least one biological remodeling agent promotesat least partial construction or at least partial reconstruction of atleast one biological tissue. In one embodiment, the at least onebiological remodeling agent includes at least one cellular or tissuescaffolding component (e.g., collagen, elastin, protein, carbohydrate,nucleic acid, organic or inorganic agent, or other component). In oneembodiment, the at least one biological remodeling agent includes atleast one cell (e.g., endogenous cell, exogenous cell, transgenic cell,progenitor cell, allogeneic cell, neonatal cell, embryonic cell, stemcell, differentiated cell, blood cell, chondrocyte, endothelial cell,hepatocyte, keratinocyte, myocyte, osteoblast, osteoclast, osteocyte,mesenchymal cell, fibroblast, etc.), other cells are described herein.(See, for example, Nolte et al., Cells Tissues Organs vol. 187, pp.165-176 (2008), which is incorporated herein by reference.)

In one embodiment, the at least one biological remodeling agent providesa scaffold or matrix for growth, regrowth, restructuring, remodeling, orphysically, chemically, or biologically structuring one or more cells orbiological tissues. In one embodiment, the at least one biologicalremodeling agent provides at least one mechanical structure to the atleast one biological tissue. In one embodiment, the at least onebiological remodeling agent provides a load-bearing structure to atleast one biological tissue.

In one embodiment, the at least one biological remodeling agent includesone or more self-organizing structures, including at least one hydrogel,nanofiber, nanoparticle, or helical structure. (See, for example, Pokroyet al, Science vol. 323, pp. 237-240 (2009); U.S. Patent ApplicationPublication No. 20080070304, each of which is incorporated herein byreference.) In one embodiment, the at least one biological remodelingagent includes one or more self-assembling nanofibers or nanoparticles.

In one embodiment, the at least one biological remodeling agent at leastpartially generates a wound dressing, such as a sheet, bandage, film, orother permeable, semi-permeable, or impermeable covering. In oneembodiment, the at least one wound dressing at least partially includesnatural, synthetic, or artificial skin, skin substitute, or skindeposit. In one embodiment, the at least one biological remodeling agentincludes at least one nanotube (such as a carbon nanotube, DNA nanotube,or other nanotube).

In one embodiment, the at least one biological remodeling agent includesat least one of an anti-tumor agent, antimicrobial agent, anti-viralagent, analgesic, antiseptic, anesthetic, diagnostic agent,anti-inflammatory agent, vaccine, cell growth inhibitor, cell growthpromoter, chemical debridement agent, immunogen, antigen, radioactiveagent, apoptotic promoting factor, angiogenic factor, anti-angiogenicfactor, hormone, enzymatic factor, enzyme, papain, collagenase,protease, peptidase, elastase, urea, vitamin, mineral, nutraceutical,cytokine, chemokine, probiotic, coagulant, anti-coagulant, phage,prodrug, prebiotic, blood sugar stabilizer, smooth muscle cellactivator, epinephrine, adrenaline, neurotoxin, neuro-muscular toxin,Botulinum toxin type A, microbial cell or component thereof, or virus orcomponent thereof. In one embodiment, the nutraceutical includes one ormore of a flavonoid, antioxidant, beta-carotene, anthocyanin,alpha-linolenic acid, omega-3 fatty acids, yeast, bacteria, algae, othermicroorganisms, plant products, or animal products.

In one embodiment, the at least one biological remodeling agent isutilized in at least partially constructing or reconstructing at least aportion of one or more biological tissues or organs. In on embodiment,the at least one biological remodeling agent assists in the repair,enhancement, or replacement of at least a portion of at least onebiological tissue structure or function. In one embodiment, the at leastone biological remodeling agent assists in restoring, maintaining, orimproving at least one tissue or organ function.

In one embodiment, at least one frozen particle composition including atleast one biological remodeling agent or adhesive agent is utilized inat least partially generating at least one biological tissue de novo. Inone embodiment, at least one frozen particle composition including atleast one biological remodeling agent or adhesive agent is utilized inat least partially repairing at least one damaged or diseased biologicaltissue. In one embodiment, the at least one damaged or diseasedbiological tissue is located in vivo. In one embodiment, the at leastone damaged or diseased biological tissue includes one or more wounds.

In one embodiment, the at least one biological remodeling agent isadministered to at least one substrate, as described herein. In oneembodiment, the at least one biological remodeling agent includes atleast one nontoxic agent. In one embodiment, the at least one biologicalremodeling agent includes a biocompatible, bioresorbable, orbiodegradable agent. In one embodiment, the at least one substrate towhich the one or more frozen particle compositions is deposited oradministered is at least one of biocompatible, bioresorbable, orbiodegradable.

In one embodiment, at least one scaffold is utilized for construction,reconstruction, or remodeling of at least one biological tissue. In oneembodiment, the at least one scaffold is at least partially generated bydeposition or administration of one or more frozen particle compositionsincluding at least one biological remodeling agent. In one embodiment,the at least one scaffold is at least one of biocompatible,bioresorbable, or biodegradable.

In one embodiment, a template or molding is utilized for deposition ofone or more frozen particle compositions including at least onebiological remodeling agent. In one embodiment, the frozen particlecomposition includes one or more of a biological remodeling agent, atherapeutic agent, abrasive, explosive material, adhesive agent, orother agent. In one embodiment, the template or molding is at least oneof nontoxic, biocompatible, bioresorbable, or biodegradable. In oneembodiment, the one or more biological remodeling agents, are depositedor administered directly onto at least one substrate that is utilized inconstructing, reconstructing, or remodeling at least one biologicaltissue.

In one embodiment, one or more frozen particle compositions, includingat least one biological remodeling agent, are delivered to at least onescaffold, including a three dimensional porous scaffold. In oneembodiment, the scaffold includes means for cell attachment, means forcell proliferation, means for cell differentiation, means for cellmigration, means for cell contracting, means for cell expression, meansfor cell matrix production, or means for cell spreading. In oneembodiment, the at least one scaffold includes seeding at least one cell(e.g., a live cell) within at least one scaffold. In one embodiment,seeding at least one cell within the at least one scaffold occurs priorto, simultaneously with, or subsequent to, at least partiallygenerating, implanting, or transplanting the at least one scaffold. Inone embodiment, the at least one scaffold includes injecting at leastone biological remodeling agent and at least one cell (e.g., a livecell) mixture to the at least one substrate for at least partiallyconstructing, reconstructing, or remodeling at least one biologicaltissue. In one embodiment, the scaffold is at least partially generated,implanted, or transplanted and is eventually seeded with a subject's owncells, either naturally or artificially.

In one embodiment, the at least one biological remodeling agent includesone or more of calcium phosphate, albumin, cytokine, pegylated cytokine,bone, cartilage, globulin, fibrin, thrombin, glutaraldehyde-crosslinkedpericardium, hide powder, hyaluronic acid, hydroxyapatite, keratin,ligament, nitinol, nucleic acid polymers, polyethylene, polylethyleneglycol, polyethylene glycol diacrylate, polyethylene terephthalatefiber, polyglycol, polylactate, polytetrafluoroethylene, polylacticacid, polyglycolic acid, polycaprolactone, PURAMATRIX™ self-assemblypeptide hydrogel fibers, linear aliphatic polyester, tendon, fibrinogen,hyaluronate, chitin, chitosan, methylcellulose, alginate, hyaluronicacid, agarose, cellulose, polyaldehyde gluronate, Factor XIII, FactorXII, silk, nylon, collagen, elastin, silicone, polyurethane, ceramicpowder, pectin, wax, glycosaminoglycan, poly(α-hydroxyacid), selectin,glutaraldehyde, hydrophobic non-glycosylated protein, hydrogel, peptidehydrogel, or gelatin.

In one embodiment, the at least one biological remodeling agent includesone or more of Type I collagen, Type II collagen, Type III collagen,Type VII collagen, or Type X collagen. In one embodiment, the at leastone biological remodeling agent includes one or more of elastin fibersor soluble elastin.

In one embodiment, the biological remodeling agent includes at least onemember of the Transforming Growth Factor β superfamily, including butnot limited to bone morphogenetic/osteogenic proteins (BMPs/OPs), growthdifferentiation factors, activin A and B, inhibin A and B,Anti-mullerian hormone, Nodal, TGF-β type receptors such as Activin TypeI receptors, Activin Type II receptors, transducers/SMAD molecules,ligand inhibitors (e.g., Cerberus, chordin, Dan, Decorin, Follistatin,Gremlin, Lefty, LTBP1, Noggin, THBS1), co-receptors (e.g.,BAMBI-Cripto), SARA, or other molecules. (See, for example, Aarabi etal., PLOS Med., vol. 4, Issue 9, pp. 1464-1470 (2007). In oneembodiment, the at least one biological remodeling agent includes one ormore of epidermal growth factor (EGF), platelet derived growth factor(PDGF), fibroblast growth factor (FGF), insulin-like growth factor(IGF-1), human growth hormone, granulocyte-colony stimulating factor(G-CSF), or granulocyte-macrophage colony-stimulating factor (GM-CSF).In one embodiment, one or more biological remodeling agents include atleast one nucleic acid. In one embodiment, one or more biologicalremodeling agents include at least one RNA or DNA molecule. In oneembodiment, the one or more biological remodeling agents include atleast one of a protein, carbohydrate, or fat.

Some other non-limiting examples of biological remodeling agents, aswell as the general but non-limiting solidification mechanism of each,are set forth in Table III below. Abbreviations include: OPF:oligo(poly(ethylene glycol) fumarate); P(CL/TMC):poly(-caprolactone-co-trimethylene carbonate); PDLLA: poly(D,L-lactide);PEG: poly(ethylene glycol); PEO: poly(ethylene oxide); PEO-PPO-PEO:polyethylene oxide-polypropylene oxide-polyethylene oxide; PhosPEG-dMA:poly(ethylene glycol)di[ethylphosphatidyl(ethylene glycol)methacrylate];PLA(Glc-Ser): Poly(L-lactic acid-co-glycolic acid-co-L-serine); PLA-PEG:poly(lactic acid)-poly(ethylene glycol; PLAL-ASP: Poly(lacticacid-co-lysine)-poly(aspartic acid); PLGA: Poly (DL-lactic-co-glycolicacid); PLLA: poly(L-lactic acid); PLLA-PEG: poly(L-lactide-ethyleneglycol); PNIPAAm: poly(N-isopropylacrylamide); P(NIPAAm-AAc):Poly(N-isopropylacrylamide-acrylic acid); PPF: poly(propylene fumarate);P(PF-co-EG): poly(propylene furmarate-co-ethylene glycol; PVA:poly(vinyl alcohol). (See, for example, Hou et al., M. Mater. Chem.,vol. 14, pp. 1915-1923 (2004), which is incorporated herein byreference.)

TABLE III Biological Remodeling Agent Solidification mechanism Calciumphosphate Ceramics setting Chitosan Thermal gelation MethylcelluloseThermal gelation Alginate Photo cross-linking or ionic gelationHyaluronic acid Photo cross-linking Agarose Thermal gelation FibrinThermal gelation Gelatin Thermal gelation Poly(aldehyde gluronate)Chemical cross-linking PEG or PEO Photo cross-linking PEO-PPO-PEOThermal gelation PEO-PLLA-PEO Photo cross-linking PLA-g-PVA Photocross-linking PEO-PLLA Thermal gelation PLGA-PEG Thermal gelationPEG-co-Poly(α-hydroxy acid) Photo cross-linking PVA, PLAL-ASP,P(CL/TMC), PLA(Glc- Photo cross-linking Ser), or Polyanhydrides PPF,OPF, or P(PF-co-EG) Photo cross-linking or radical polymerizationPhosPEG-dMA Photo polymerization PNIPAAm-PEG, PNIPAAm-gelatin, Thermalgelation P(NIPAAm-AAc) PEG based hydrogels Enzymatic cross-linking orMichael-type addition reaction PLA-PEG-biotin Self-assemblySubstrates

In one embodiment, the one or more frozen particle compositions areadministered or delivered to at least one substrate. In one embodiment,the at least one substrate includes at least one nontoxic,biodegradable, bioresorbable, or biocompatible substrate. In oneembodiment, the at least one substrate includes one or more of a cell,tissue, organ, structure, or device. In one embodiment, the substrateincludes at least a portion of which is naturally, artificially, orsynthetically derived. In one embodiment, the substrate includes atleast a portion of which is genetically altered. In one embodiment, thestructure or device may include a prosthesis, cell matrix, tissuematrix, supplement, implement, bandage, tourniquet, wound dressing,splint, stent, patch, gauze, covering, shunt, needle, scalpel, matrix,sponge, mesh, woven fabric, knitted fabric, film, instrument, or othertool or item. (See, for example, U.S. Patent Application Publication No.20070021816, which is incorporated herein by reference.) In oneembodiment, the device includes at least one mechanical or electricaldevice. In one embodiment, the substrate includes at least oneimplantable substrate.

In one embodiment, the substrate is located in at least one of in situ,in vitro, in vivo, in utero, in planta, in silico, or ex vivo. In oneembodiment, the at least one substrate is transplanted or implanted intoat least one subject. In one embodiment, the at least one substrate isingested by at least one subject. In one embodiment, the at least onesubstrate includes at least one biological tissue from at least onedonor or recipient. In one embodiment, the at least one donor includesat least one cadaver.

In one embodiment, the substrate includes, but is not limited to,biological tissue as described herein. For example, biological tissueincludes soft tissues (such as connective tissue, or other soft tissue),or hard tissues (including calcified tissues, such as bone or teeth). Inone embodiment, a cell includes, but is not limited to, at least one ofan autologous cell, allogenic, xenogenic, stem cell, or syngenic cell.The one or more cells may include endogenous or exogenous cells relativeto a particular subject. In one embodiment, the at least one substrateincludes one or more stem cells (e.g., hematopoietic stem cells,adipocyte stem cells, neuronal stem cells, embryonic stem cells, hepaticstem cells, dermal stem cells, pancreatic stem cells, stem cells relatedto bone, stem cells related to muscle, or others). Particular examplesof cells and biological tissues are described herein at other sections.

In one embodiment, the at least one biological tissue includes but isnot limited to, one or more of skin, scalp, hair, nail, nail bed, teeth,eye, ear, ovary, oviduct, tongue, tonsil, adenoid, liver, bone,pancreas, stomach, blood vessel, bone marrow, blood, lymph, heart, lung,brain, breast, kidney, bladder, urethra, ureter, gall bladder, uterus,prostate, testes, vas deferens, fallopian tubes, large intestine, smallintestine, esophagus, oral cavity, nasal cavity, otic cavity, connectivetissue, muscle tissue, or adipose tissue. In one embodiment, the atleast one tissue includes one or more of a tendon, vein (e.g., femoralor saphenous vein), artery, or capillary. In one embodiment, the atleast one biological tissue includes a mucosal surface. In oneembodiment, the at least one biological tissue includes one or more of aplant part. In one embodiment, the at least one biological tissueincludes one or more of a stalk, stem, leaf, root, or tendril.

In one embodiment, the treatment of at least one biological tissueincludes one or more of ossicular chain reconstruction in otlogicsurgery, nerve anastomosis (e.g. peripheral nerve anastomosis);cerebralspinal fluid sealing in neurological repair, vascular repair oranastomosis, ocular repair, gastrological repair, urological repair,skin closure, bronchial repair (e.g. bronchial stump leakage), alveolarrepair, or dental fillings. In one embodiment, the at least onebiological tissue includes fetal tissues or organs (e.g. in utero) andcan include any of the tissues or organs described herein.

In one embodiment, the at least one biological tissue is located in atleast one tissue or organ related to transplantation. In one embodiment,transplantation includes extraction or implantation of the at least onetissue or organ. In one embodiment, the at least one tissue or organrelated to transplantation is extracted from at least one firstbiological source or subject and implanted into at least one secondbiological source or subject. In one embodiment, the at least one tissueor organ related to transplantation is cultured prior to implantation ina subject. In one embodiment, the tissue or organ related totransplantation is an artificial tissue or organ (e.g. a bladder, heart,kidney, liver, pancreas, skin, eye, lung, nerve, blood vessel, andothers). In one embodiment, the tissue or organ related totransplantation involves at least two sources (i.e. multiple species,partially artificial or synthetic, multiple biological cells or tissuesincluding stem cells). In one embodiment, the at least one tissue ororgan related to transplantation includes at least one donor orrecipient tissue or organ.

In one embodiment, the at least one substrate includes at least one cellmass. In one embodiment, the at least one cell mass includes at leastone of a scar, pore, pit, eschar, granuloma, keloid, artheromatousplaque, abscess, pustule, scaling (e.g., psoriasis or eczema), infectedtissue, hair follicle, necrotic tissue, stratum corneum, wrinkle, wound,tumor, skin structure, nevus, cyst, lesion, callus, neoplastic tissue,gangrenous tissue, or cellular deposit. In one embodiment, the at leastone cell mass includes at least one benign or malignant tumor. In oneembodiment, the at least one benign or malignant tumor relates to one ormore of a melanoma, lymphoma, leukemia, sarcoma, blastoma, or carcinoma.

In one embodiment, the at least one cell mass is related to at least oneblood clot, microorganism accumulation, blood vessel obstruction, ductobstruction, bowel obstruction, infection, gangrene, connective tissuedestruction, tissue or organ damage, injury, white blood cellaccumulation, or cancer.

In one embodiment, the at least one substrate includes one or morewounds. In one embodiment, the one or more wounds are located in atleast one biological tissue or organ. In one embodiment, the one or morewounds are located in one or more of skin tissue, muscle tissue, eyetissue, nervous tissue, peritoneal tissue, an organ, connective tissue,neoplastic tissue, or bone tissue.

In one embodiment, the one or more wounds are located in at least onesubject. The one or more wounds include but are not limited to at leastone of an incision (including surgical incision such as for facial orother aesthetic construction or reconstruction, or other cranio-facialsurgeries, laproscopic procedures, birthing assistance, or othersurgical procedures), fracture, irritation, episiotomy, laceration,endovascular occlusion (e.g., aneurism), blood vessel anastomosis, nerverepair, abrasion, cerebral spinal fluid leak, puncture wound,penetration wound, gunshot wound, iatrogenic wound, severing, infection,ulcer, pressure sore, lesion, chemical burn (including but not limitedto exposure to an irritant, plant, or synthetic chemical), dentalcaries, first-degree burn, second-degree burn, third-degree burn,fourth-degree burn, fifth-degree burn, or sixth-degree burn. In certaininstances, the wound can be a result of a bite, such as a bite from ananimal, insect, or arachnid.

In one embodiment, the at least one subject includes one or more of avertebrate or invertebrate, insect cells, insects, bacteria, algae,plankton, or protozoa. In one embodiment, the at least one subjectincludes one or more of a reptile, mammal, amphibian, bird, or fish. Inone embodiment, the at least one subject includes at least one human. Inone embodiment, the at least one subject includes at least one oflivestock, pet, zoo animal, undomesticated herd animal, wild animal, orproduct animal.

In one embodiment, the at least one subject includes at least one of asheep, goat, frog, dog, cat, rat, mouse, vermin, monkey, duck, horse,cow, pig, chicken, shellfish, fish, turkey, llama, alpaca, bison,buffalo, ape, primate, ferret, wolf, fox, coyote, deer, rabbit, guineapig, yak, chinchilla, mink, reindeer, elk, camel, fox, elk, deer,raccoon, donkey, or mule.

Detectable Materials

In one embodiment, the one or more frozen particle compositions includeat least one of a polymer, biopolymer, nanoparticle, sensor,micro-syringe, circuit, or detection material. Such dectable materialmay allow for visualization of the one or more frozen particlecompositions, the administration process, or provide other benefits(including but not limited to reinforcement, adhesive, biologicalremodeling, abrasive, explosive, or therapeutic benefits). In oneembodiment, the nanoparticle includes one or more of a nanorod,nanobone, nanocapsule, or other particle. In one embodiment, thenanoparticle releases its payload when exposed to an energy source,including heat or light. In one embodiment, the nanoparticles have atime-release payload of, for example, one or more therapeutic agents,adhesive agents, biological remodeling agents, reinforcement agents,abrasives, explosive materials, or other agents.

In certain instances, the detection material can be located on or in theone or more frozen particle compositions, or it can be intermixed withthe one or more frozen particle compositions. In certain instances, thedetection material provides a “tracer” agent that allows forvisualization of one or more locations of administration of the at leastone composition, or the at least one frozen particle. In certaininstances the detection material is located on the at least one frozenparticle composition or the at least one frozen particle. In otherinstances, the detection material is separate from the at least onefrozen particle composition or the at least one frozen particle. Incertain instances, the detection material forms a mixture with thefrozen particle composition or frozen particles. In certain instances,the detection material is separate from the one or more frozen particlecompositions and is administered at approximately the same time, inapproximately the same place, or in approximately the same manner as theone or more frozen particle compositions. In one embodiment, thedetectable material is located in at least one cavity or compartment ofthe one or more frozen particle compositions.

In one embodiment, detection material includes a detectable labelincluding but not limited to, a calorimetric label, a radioactive label,a light-emitting label (such as a luminescent compound, a fluorescentcompound, a phosphorescent compound, or a quantum dot), a nucleic acidlabel, a protein label, an antibody label, a ligand label, a receptorlabel, a magnetic label, or other detectable label. In one embodiment,the at least one detection material includes but is not limited to, atleast one electronic identification device. In one embodiment, the atleast one electronic identification device includes at least one radiofrequency identification device.

In one embodiment, the at least one detection material includes but isnot limited to, at least one radioactive element. In one embodiment, theradioactive element includes but is not limited to, ³²P, ³⁵S, ¹³C, ¹³¹I,¹⁹¹Ir, ¹⁹²Ir, ¹⁹³Ir, ²⁰¹Tl, or ³H. In one embodiment, the at least onedetection material includes at least one radioactive, luminescent,colorimetric or odorous substance. In one embodiment, the at least onecalorimetric substance includes one or more of an inorganic, organic,biological, natural, artificial, or synthetic substance. Thecalorimetric or luminescent substance may include, but not be limited toa dye, pigment, or a light-emitting substance, such as a luminescentsubstance, a fluorescent substance, phosphorescent substance, or quantumdot. In one embodiment, the at least one colorimetric or luminescentsubstance is nontoxic, biocompatible, bioresorbable, or biodegradable.

Some examples of colorimetric or luminescent substances include, but arenot limited to, colored agents that have an affinity for a cell ortissue, such as acid dyes (e.g., water-soluble anionic dyes), basic dyes(e.g., water-soluble cationic dyes), direct or substantive dyes (e.g.,stains for nucleic acids, proteins, lipids, carbohydrates, cellpopulations, tissues, or organelles), mordant dyes, vat dyes, reactivedyes, disperse dyes, azo dyes, sulfur dyes, food dyes, solvent dyes,carbene dyes, or others. Some examples of chromophores that can beutilized include, but are not limited to, dyes that are based on orderivatives of acridine, anthraquinone, arymethane (e.g., diphenylmethane, triphenyl methane), —N═N azo structure, phthalocyanine,diazonium salts, —NO₂ nitro functional group, —N═O nitroso functionalgroup, phthalocyanine, quinine, azin, eurhodin, safranin, indamin,indophenol, oxazin, oxazone, thiazin, thiazole, xanthene, fluorine,pyronin, fluorine, rhodamine, or others. In one embodiment, thecolorimetric substance includes trypan blue.

In one embodiment, the colorimetric or luminescent substance includesone or more fluorescent tags, including but not limited to fluorescein,phycobilin, phycoerythrin, phycourobilin, chlorophyll, phycocyanin,allophycocyanin, green fluorescent protein, or others. In oneembodiment, the luminescent substance includes at least onelight-emitting substance, including but not limited e.g. bioluminescentsubstances, chemiluminescent substances, luciferin, isoluminol,luminescent minerals, etc.

In one embodiment, the at least one detection material includes but isnot limited to, at least one of a diamagnetic particle, ferromagneticparticle, paramagnetic particle, super paramagnetic contrast agent, orother magnetic particle.

Some non-limiting examples of particular diamagnetic substances includewood, water, organic compounds (such as petroleum), metals (includingcopper, mercury, gold, bismuth), or benzoic acid.

Methods, Devices, Systems

As described herein, a device or machine (including a computer) may beutilized in various aspects relating to compositions, methods, orsystems relating to one or more frozen particle compositions.Non-limiting examples of such aspects may include predicting orcalculating various properties or characteristics relating to the one ormore frozen particle compositions, any substrate, any subject, anyadministration device, or any administration protocol.

In one embodiment, a method is disclosed for making one or more frozenparticle compositions, optionally including at least one agent. In oneembodiment, a method is disclosed for administering or delivering one ormore frozen particle compositions. One or more methods disclosed includecomputer-implemented methods.

In one embodiment, a method comprises administering at least one frozenparticle composition including at least one agent to a substrate. In oneembodiment, may provide promoting wound healing; promoting healing ofskin, cartilage, or bone; filling of skin wrinkles or flaws; filling ofconnective tissue; treating vesico-ureteral reflux; treating urinaryincontinence; fixing prostheses or materials to at least one biologicaltissue; or producing at least one film, gel, or membrane for use invitro or in vivo to assist in a biological function.

In one embodiment, a method of providing at least one agent, such as abiological remodeling agent, to at least one substrate comprisesadministering one or more frozen particle compositions to at least onesubstrate, wherein the one or more frozen particle compositions includeat least one biological remodeling agent as described herein. In oneembodiment, a method of at least partially constructing or at leastpartially reconstructing at least one biological tissue or organcomprises administering one or more frozen particle compositions thatinclude at least one agent (such as at least one of a biologicalremodeling agent, adhesive agent, therapeutic agent, reinforcementagent, abrasive, or explosive material) in such a manner that the atleast one agent is deposited. In one embodiment, the method furtherincludes abrading or ablating one or more surfaces of the at least onesubstrate prior to, during, or subsequent to the administering of theone or more frozen particle compositions. In one embodiment, the methodof administering one or more frozen particle compositions is provided insuch a manner as to induce at least one cellular event. In oneembodiment, the at least one cellular event includes one or more of:cell migration, cell attachment, cell retention, cell differentiation,cell proliferation, apoptosis, diffusion of materials, angiogenesis,nucleic acid expression, protein translation, protein modification,carbohydrate production, carbohydrate secretion, protein secretion, fatproduction or fat secretion. In one embodiment, the method furtherincludes administering at least one component including an optical,photonic, or electronic article. In one embodiment, the at least onearticle is configured to communicate with at least one computer system.In one embodiment, the at least one article is configured to monitor atleast one characteristic of the at least one biological tissue.

In one embodiment, computer-aided tissue engineering (CATE) is utilizedin the design (including tissue scaffold design), image processing,predicting, modeling, simulation, manufacturing, administration ordelivery of at least one frozen particle composition, informatics(including computer-aided tissue classification and application fortissue identification and characterization at different tissuehierarchical levels), or other aspects of tissue reconstruction with oneor more frozen particle compositions described. In one embodiment,computer-aided tissue engineering compares information regarding atleast one of design, image processing, predicting, modeling, simulation,manufacturing, administration or delivery of at least one frozenparticle composition, or informatics for at least one biological tissuewith at least one dataset or database. In one embodiment, a dataset ordatabase is generated from information regarding at least one of design,image processing, predicting, modeling, simulation, manufacturing,administration or delivery of at least one frozen particle composition,informatics, or other aspect of tissue reconstruction with one or morefrozen particle compositions described.

In one embodiment, ink-jet printing is utilized for stereo-modelfabrication, or for direct biological tissue construction,reconstruction, or remodeling through deposition or administration ofone or more frozen particle compositions. (See, for example, Mironov, etal, Trends in Biotech. Vol. 21, No. 4; pp. 157-161 (2003), which isincorporated herein by reference.) In one embodiment, the one or morefrozen particle compositions include one or more agents that fuse uponadministration or deposition. (See, for example, Jakab, et al, TissueEng. Part A, Vol. 14, No. 3 pp. 413-421 (2008), which is incorporatedherein by reference.)

In one embodiment, at least one of rapid prototyping (including but notlimited to stereolithography), fused deposition modeling,three-dimensional printing, selective deposition modeling, solidfree-form fabrication (SFF), selective laser sintering, laminated objectmanufacturing, gas foaming, solvent casting and particulate leaching,emulsification, freeze-drying, phase separation, shape depositionmanufacturing, or other method is utilized with administration of one ormore frozen particle compositions for tissue reconstruction. (See, forexample, U.S. Patent Application Publication No. 20040075196; Barry, etal., Phil. Trans. R. Soc. A vol. 364, pp. 249-261 (2006); and U.S.Patent Application Publication No. 20080145639, each of which isincorporated herein by reference.) In one embodiment, a model is usedfor designing or developing the architecture of the at least onebiological tissue prior to administering or depositing the one or morefrozen particle compositions for at least partially constructing, atleast partially reconstructing, or at least partially remodeling atleast one biological tissue. In one embodiment, the one or more frozenparticle compositions are administered or deposited directly onto atleast one substrate for at least partially constructing, at leastpartially reconstructing, or at least partially remodeling at least onebiological tissue. In one embodiment, the at least partialreconstruction, at least partial construction, or at least partialremodeling of at least one biological tissue includes depositing atleast one agent of at least one frozen particle composition. In oneembodiment, the at least partial reconstruction, at least partialconstruction, or at least partial remodeling of at least one biologicaltissue includes at least partially abrading or ablating at least onesurface of at least one substrate (e.g., biological tissue) with atleast one frozen particle composition.

In one embodiment, sample cells are grown ex vivo, introduced withscaffold in the appropriate environment for cell or tissue growthutilizing one or more frozen particle compositions, and the cellsimplanted or transplanted into at least one subject. (See, for example,Sun et al., Biotechnol. Appl. Biochem. vol. 39, pp. 29-47 (2004), whichis incorporated herein by reference.)

Computer-aided tissue modeling utilized in conjunction with certainembodiments for administration of one or more frozen particlecompositions includes imaging data acquisition. For example, a medicalimaging modality must be capable of one or more of producingthree-dimensional views of anatomy, differentiating heterogenous tissuetypes and displaying the vascular structure, as well as generatingcomputational tissue models.

In one embodiment, computer-aided tissue modeling utilized inconjunction with certain embodiments for administration of one or morefrozen particle compositions includes generating at least one of atwo-dimensional plot or a three-dimensional model. In one embodiment, atwo-dimensional plot or three-dimensional view of anatomical modelingincludes one or more of geometry, morphology, volumetric representation,mechanical, deformation, kinematic modeling, contour-based modeling,surface extraction, or solid modeling. In one embodiment, anatomicalmodeling occurs by way of computer-assisted tomography (CAT) or computedtomography (CT) scan, positron emission tomography (PET) scan,magnetic-resonance imaging (MRI), ultrasound, electrical-impedancemonitoring, x-ray, microscopy, multiphoton calcium-imaging, or otherimaging technique or device. (See, for example, Girod et al, J.Cranio-Max. Surgery vol. 29, pp. 156-158 (2001), which is incorporatedherein by reference.) In one embodiment, multiple three-dimensionalimages are assembled or integrated for modeling of the tissue or organ.

Computer-aided tissue information utilized in conjunction withadministration of one or more frozen particle compositions includes oneor more of cell or tissue classification, hard tissue classification,soft tissue classification, tumor diagnosis, morphometric or cytometricinformation, tumor cell detection, tissue properties, cell aggregation,cell or tissue growth, cell to cell interaction, or cell to tissueinteraction.

In one embodiment, at least one computer system is configured to provideone or more instructions to one or more devices for deposition oradministration of one or more frozen particle compositions. In oneembodiment, at least one device is configured to deposit or administerone or more frozen particle compositions on any x, y, or z axis. In oneembodiment, the at least one computer system provides one or moreinstructions for predicting, controlling, or varying the administrationof one or more frozen particle compositions or deposition of at leastone agent included in the one or more frozen particle compositions onany x, y, or z location. In one embodiment, the at least one computersystem provides one or more instructions for temporal, spatial, orregional locations for deposition or administration of one or morefrozen particle compositions. Other components of the at least onecomputer system or device are included in the figures as described.

Computer-aided tissue scaffold design and manufacturing utilized inconjunction with certain embodiments for administration of one or morefrozen particle compositions includes one or more of tissue scaffoldmodeling, biomimetic design, tissue scaffold fabrication, hybridscaffold and cells, cell pattern, printing and deposition, or blueprintand organ hierarchical modeling. For example, in one embodiment, atleast one parameter for at least partially constructing, at leastpartially reconstructing, or at least partially remodeling at least onetissue that are considered in design and administration of one or morefrozen particle compositions, includes one or more of porosity, poresize, interconnectivity, transport properties, cell-tissue formation,mechanical strength, facilitation of attachment or distribution, growthof regenerative tissue and facilitate the transport of nutrients orother factors.

In one embodiment, the one or more frozen particle compositions areadministered to at least one substrate by way of biopolymer depositionlayering. For example, technology related to a micronozzle-based layeredmanufacturing, a microsyringe-based deposition, three dimensionalplotting (e.g., Bioplotter, Envision Tech., Marl, Germany), ormicromolding (e.g., by vacuum-molding) are capable of being utilizedwith the one or more frozen particle composition deposition. (See, forexample, U.S. Patent Application Publication No. 20060195179.)

In one embodiment, the reconstructed tissue manufactured by use of oneor more frozen particle compositions includes at least one material thatmimics natural structures or functions, or enhances natural tissuegrowth. For example, in one embodiment, one or more frozen particlecompositions are included in “smart” tissue scaffolds including one ormore of a sensor, syringe, therapeutic agent, electronic article,nano-scale device, micro-scale device, or feedback mechanism. Forexample, at least one biosensor, circuit, or other electronic articlecan be included for monitoring tissue growth, dissolution,deterioration, biochemical function, structural integrity or function,immunological reaction, or other activities or conditions; or forproviding a feedback mechanism. In one embodiment, the at least oneoptical, photonic, or electronic article included in the at least onetissue or organ is capable of communicating with at least one computersystem.

In addition, one or more agents are included in one embodiment of thetissue reconstructed with one or more frozen particle compositions. Suchagents include at least one of a therapeutic agent, abrasive, explosivematerial, adhesive agent, reinforcement agent, biological remodelingagent, one or more cells, or other agent. In one embodiment, thereconstructed or remodeled tissue includes at least one gene-activatedmatrix that allows for incorporation of one or more specific genes whenone or more cells are administered to the matrix, or are allowed tomigrate to the matrix. In one embodiment, one or more frozen particlecompositions are utilized in three-dimensional cell or organ printing.

As described herein, in one embodiment the at least one biologicalremodeling agent includes one or more of: scaffolding materials, cells,nutrients, growth factors, or other components for at least partiallyconstructing at least one tissue or organ de novo. (See Sun, et al,Ibid.)

In one embodiment, a scaffold is constructed, at least in part byseeding living cells into the scaffold. As described herein, variousmaterials are capable of being utilized as a scaffold by delivering oneor more frozen particle compositions, or deposition of at least oneagent included in one or more frozen particle compositions. Inparticular, materials including but not limited to, pastes, resins,gels, bone cements, cellulose, silicone, polyurethanes, hydrogels,chitosan, or ceramic powders can be used.

Also as described herein, one or more materials utilized for thescaffold can be used for cell seeding, delivery systems for one or moretherapeutic agents, other agents, or for integrating one or moreangiogenic factors, growth factors, cytokines, or other agents.

In one embodiment, a composition includes an ex vivo biological tissueor organ that is at least partially constructed or at least partiallyreconstructed by administering one or more frozen particle compositions.In one embodiment, the one or more frozen particle compositions includeat least one of a therapeutic agent, adhesive agent, biologicalremodeling agent, explosive material, abrasive, or reinforcement agent.

In one embodiment, the ex vivo biological tissue or organ is at leastpartially constructed or at least partially reconstructed de novo byadministering one or more frozen particle compositions. In oneembodiment, the one or more frozen particle compositions areadministered to at least one substrate. In one embodiment, the at leastone substrate includes one or more of a cell, tissue, organ, structure,or device. In one embodiment, the composition further includes at leastone article including an optical, photonic, or electronic article. Inone embodiment, the at least one article is configured to communicatewith at least one computer system. In one embodiment, the at least onearticle is configured to monitor at least one characteristic of the atleast one biological tissue or organ. In one embodiment, the at leastone characteristic of the at least one biological tissue or organincludes one or more of: tissue formation, tissue growth, cellproliferation, cell differentiation, apoptosis, dissolution,deterioration, biochemical function of at least one cell, biochemicalfunction of at least one tissue, biochemical function of at least oneorgan, structural integrity, structural function, immunologicalreaction, or durability of the at least one biological tissue or organ.In one embodiment, the at least one characteristic of the at least onebiological tissue or organ includes one or more of: tissue formationassociated with at least one substrate, tissue growth associated with atleast one substrate, cell proliferation associated with at least onesubstrate, cell differentiation associated with at least one substrate,apoptosis associated with at least one substrate, dissolution associatedwith at least one substrate, deterioration associated with at least onesubstrate, biochemical function of at least one cell or tissueassociated with at least one substrate, structural integrity of at leastone substrate, structural function of at least one substrate,immunological reaction to at least one substrate, or durability of atleast one substrate.

In one embodiment, a composition comprises a support means for aiding inat least partially constructing or at least partially reconstructing atleast one biological tissue or organ; and one or more frozen particlecompositions as described herein. In one embodiment, the one or morefrozen particle compositions include at least one biological remodelingagent, adhesive agent, explosive material, abrasive, reinforcementagent, or therapeutic agent. In one embodiment, the support meansincludes at least one substrate configured for biological tissueformation or tissue growth. In one embodiment, the support meansincludes one or more of a cell scaffold, a tissue scaffold,extracellular matrix, methylcellulose, agarose, cellulose, a cell, apolymer, or other substrate. In one embodiment, the support meansincludes at least one substrate configured for promoting one or more of:cell migration, cell attachment, cell retention, cell differentiation,cell proliferation, apoptosis, diffusion of materials, angiogenesis,nucleic acid expression, protein translation, protein modification,protein secretion, carbohydrate production, carbohydrate secretion, fatproduction, or fat secretion.

In one embodiment, the one or more frozen particle compositions aredeposited on a pre-existing substrate scaffolding, such as a flat orhoneycomb film. (See, for example, Nishikawa et al., Mat. Res. Soc.Symp. Proc. Vol. 724 pp, N11.7.1-N11.7.6 (2002).) In one embodiment, atleast one agent included in one or more frozen particle compositions aredeposited such that the scaffolding is formed entirely from suchdeposition.

In one embodiment, the one or more frozen particle compositions includeone or more cells. In one embodiment, the one or more cells aredeposited during administration of the one or more frozen particlecompositions. In one embodiment, the one or more frozen particlecompositions are administered to at least one substrate. In oneembodiment, the one or more cells serve particular functions. In oneembodiment, the one or more cells serve at least one function including:seeding the scaffold, populating the tissue, reducing an immunereaction, facilitating tissue function, promoting cellular or tissueformation, promoting cellular or tissue proliferation, promotingcellular or tissue differentiation, promoting cellular or tissueapoptosis, modulating diffusion of materials, or increasing tissuegrowth.

In one embodiment, at least one scaffold, or other substrate is at leastpartially generated in at least one of in vitro, in vivo, ex vivo, inutero, or in planta. In one embodiment, one or more cells are utilizedfor seeding at least one scaffold in at least one of in vitro, in vivo,ex vivo, in utero, or in planta. In one embodiment, the scaffold orother substrate is at least partially generated in at least one of invitro, in vivo, ex vivo, in utero, or in planta, and subsequently istransplanted or implanted into at least one subject. In one embodiment,the subject includes the same subject in which the scaffold or othersubstrate was at least partially generated. In one embodiment, whereinthe scaffold or other substrate is transplanted or implanted, thescaffold or other substrate is modified in vitro, in vivo, ex vivo, inutero, or in planta prior to transplantation or implantation into atleast one subject. In one embodiment, the at least one scaffold or atleast one remodeled or reconstructed tissue is transplanted or implantedone or more times. In at least on embodiment, at least one substrate,including at least one tissue scaffold, is at least partially generatedin vivo, and subsequently relocated within the same subject. (See, forexample, Ripamonti et al., J. Anat. Vol. 209, pp. 447-468 (2006), whichis incorporated herein by reference.)

In one embodiment, construction, reconstruction, or remodeling of atleast one biological tissue or organ includes at least one of designinga blueprint or model. In one embodiment, the blueprint or model includesa software representation containing bio-information, physical ormaterial information, or anatomic or geometric information. In oneembodiment, the blueprint or model includes a process model, including asoftware representation that contains the printing operation controlcommands, process planning, or toolpath generated for the blueprint ormodel and machine hardware and control system. In one embodiment, theblueprint or model includes a process machine, including at least one ofa hardware representation that is capable of printing; and a tissue ororgan culture system that is capable of maintaining or growing theprinted living biological tissues. In one embodiment, the threedimensional organ or tissue printing with one or more frozen particlecompositions includes at least one of pre-processing or developing plotsor blueprints for the tissue or organ; processing or actual organprinting; or post-processing or organ conditioning and accelerated organmaturation.

In one embodiment, the blueprint or model includes a description orrepresentation of details of organ anatomy, morphology, tissueheterogeneity, or vascular systems at different tissue or organorganizational scales. In one embodiment, deposition of at least onetissue remodeling agent includes a process planning program controlsystem. In one embodiment, a toolpath program is included. In certaininstances, the blueprint or model provides at least one description ofthe anatomy, geometry, internal architecture of an organ or tissue ofinterest (including tissue heterogeneity), individual tissue geometryand boundary distinction within the tissue or organ of interest; atleast one definition of vascular networks and three dimensional topologyin an organ of interest; or at least one database of information basedon organ or tissue geometry, heterogeneity, and vascular network usedfor toolpath or other program generation of three-dimensional cell ororgan printing.

In one embodiment, the blueprint or model is constructed from threedimensional organ anatomy, tomography, or geometry information providedby medical imaging data (for example, as provided for by CT, PET, MRI,ultrasound, x-ray, multiphoton calcium-imaging, or other imaging). Suchimages can be modified, simulated, transformed, processed (e.g.,electronically processed), or modeled by a computer system, including bycomputer program, such as NURBS, polygonal modeling, or splines andpatches modeling. (See, for example, Sun et al, Ibid.) For example,Boolean, scaling, Gaussian smoothing, homomorphic filtering, parametricestimation techniques, Monte Carlo simulations, wavelet based methods,smoothing, mirroring, gradient weighted partial differential equationsmoothing (PDE), or other operations can be used to modify a CAD orother design. (See, for example, U.S. Patent Application Publication No.20060233454, and U.S. Pat. No. 7,353,153, U.S. Pat. No. 7,212,958; eachof which is incorporated herein by reference.) In one embodiment, acomputer system utilized in at least partial tissue construction,reconstruction, or remodeling includes at least one software programinterface to convert the CAD design or device into a heterogeneousmaterial or assembly for formation of the tissue or organ by depositionof at least one agent included in one or more frozen particlecompositions, or administration of one or more frozen particlecompositions. (See, for example, U.S. Patent Application Publication No.20060105011, which is incorporated herein by reference.)

In one embodiment, one or more adjacent areas of constructed orreconstructed tissues or organs include similar biological remodelingagents. In one embodiment, one or more adjacent areas of constructed orreconstructed tissues or organs include different biological remodelingagents. In one embodiment, one or more substrate scaffolds are utilizedto at least partially construct, at least partially reconstruct, or atleast partially remodel at least one tissue or at least one organ. Inone embodiment, the one or more substrate scaffolds include lowmicroporosity, for strong structural or mechanical load, while one ormore adjacent areas include high microporosity as well as embeddedangiogenic factors, cytokines, cells, or other agents for seeding thestructural component(s).

In one embodiment, three-dimensional CAD based models of the desiredtissue are capable of being modified by Boolean operations, or separatedinto components or elements that each are independently exportable tofreeform-fabrication technologies. In one embodiment, heterogeneousblocks are assembled brick-like into a tissue or organ. In oneembodiment, solid structural models are manufactured out of substratematerials including for example, quartz or Teflon®. The models are theninfiltrated with vasculature, living tissue, cells, or other agents.(See, for example, Sun et al, Ibid.)

In one embodiment, a method includes accepting a first input associatedwith at least one characteristic of at least one biological tissue to beat least partially constructed or at least partially reconstructed;accepting a second input associated with at least one parameter of atleast partially constructing or at least partially reconstructing the atleast one biological tissue by administering one or more frozen particlecompositions including at least one agent; and processing results of thefirst input and the second input. In one embodiment, the method isimplemented by a computer, including a computer system.

In one embodiment, the processing results of the first input and thesecond input includes electronically processing results of the firstinput and the second input. In one embodiment, the processing results ofthe first input and the second input includes electronically processingresults of the first input and the second input by utilizing one or moreof Gaussian smoothing, scaling, homomorphic filtering, parametricestimation techniques, Boolean operations, Monte Carlo simulations,wavelet based techniques, mirroring, smoothing, gradient weightedpartial differential equation smoothing, NURBS, polygonal modeling,splines and patches modeling, or modification of a CAD design.

In one embodiment, the at least one agent includes one or more of atherapeutic agent, adhesive agent, abrasive, reinforcement agent,explosive material, or biological remodeling agent. In one embodiment,the administering one or more frozen particle compositions includesadministering the one or more frozen particle compositions to at leastone substrate. In one embodiment, the at least one substrate includesone or more of a cell, tissue, organ, structure, or device.

In one embodiment, the first input includes one or more values relatedto the at least one characteristic of at least one biological tissue. Inone embodiment, the first input includes one or more spatial addressesassociated with the at least one characteristic of at least onebiological tissue. In one embodiment, the first input includes one ormore of x, y, or z coordinates associated with the at least onecharacteristic of at least one biological tissue. In one embodiment, theat least one characteristic of at least one biological tissue to beconstructed or reconstructed includes one or more of: morphologicalfeature, anatomical feature, histological feature, tissue hierarchicallevel, scaffold feature, vascular structure feature, heterogenous tissuefeature, mechanical feature, volumetric feature, geometric feature,volumetric representation, mechanical feature, deformation, kinematicfeature, surface contour feature, cytometric feature, cell aggregation,cell growth, cell-cell interaction, cell-tissue interaction, biomimeticdesign, cell pattern, cell deposition, organ hierarchical level, tissuemicrostructure, cellular microstructure, cell junction feature, tissuejunction feature, cell-tissue classification, hard tissueclassification, soft tissue classification, tumor diagnosis, or otherfeature.

In one embodiment, the first input includes one or more temporaladdresses associated with the at least one characteristic of at leastone biological tissue. In one embodiment, the first input includes oneor more values derived from at least one image of the at least onebiological tissue. In one embodiment, the at least one image includesone or more images acquired by one or more of optical coherencetomography, computer-assisted tomography scan, computed tomography,magnetic resonance imaging, positron-emission tomography scan,ultrasound, x-ray, electrical-impedance monitoring, microscopy,spectrometry, flow cytommetry, radioisotope imaging, thermal imaging,multiphoton calcium-imaging, photography, or in silico generation.

In one embodiment, the at least one characteristic of at least onebiological tissue includes one or more of cellular type, cellularfunction, cellular size, cellular constitution, cellular architecture,cellular durability, cellular source, tissue type, tissue constitution,tissue size, tissue shape, tissue function, tissue architecture, tissuesource, tissue durability, organ type, organ constitution, organ size,organ shape, organ function, organ architecture, organ source, or organdurability. In one embodiment, the at least one biological tissue islocated in at least one of in situ, in vitro, in vivo, in utero, inplanta, in silico, or ex vivo. In one embodiment, the at least onebiological tissue is at least partially located in at least one subject.

In one embodiment, the method further comprises accepting a third inputassociated with at least one feature of the at least one subject. In oneembodiment, the at least one feature of the at least one subjectincludes one or more of age, gender, genotype, phenotype, proteomicprofile, or health condition.

In one embodiment, the first input includes one or more values derivedfrom at least one image of the at least one biological tissue at leastpartially located in at least one subject. In one embodiment, theprocessing results of the first input and the second input includesdetermining at least one parameter of at least partially constructing orat least partially reconstructing the at least one biological tissuewith one or more frozen particle compositions from one or more valuesderived from at least one image of the at least one biological tissue.

In one embodiment, the second input includes one or more values relatedto the at least one parameter of at least partially constructing or atleast partially reconstructing the at least one biological tissue byadministering one or more frozen particle compositions to the at leastone substrate. In one embodiment, the at least one parameter of at leastpartially constructing or at least partially reconstructing the at leastone biological tissue includes one or more of porosity of the at leastone substrate, pore size of the at least one substrate,interconnectivity of the pores of the at least one substrate, transportproperties of the at least one substrate, cell-tissue formation of theat least one substrate, mechanical strength of the at least onesubstrate, ability for attachment or distribution of the at least oneagent included in the one or more frozen particle compositions to the atleast one substrate, ability for attachment or distribution of one ormore cells or tissues to the at least one substrate, facilitation of atleast one nutrient, or tissue formation or tissue growth associated withthe at least one substrate.

In one embodiment, the one or more values related to the at least oneparameter of constructing or reconstructing the at least one biologicaltissue includes one or more predictive values. In one embodiment, the atleast one parameter of at least partially constructing or at leastpartially reconstructing the at least one biological tissue byadministering one or more frozen particle compositions includes one ormore of: design of plot or model for administration of one or morefrozen particle compositions, constitution of the one or more frozenparticle compositions, formulation of the one or more frozen particlecompositions, size of the one or more frozen particle compositions,shape of the one or more frozen particle compositions, angle ofadministration of the one or more frozen particle compositions, velocityof administration of the one or more frozen particle compositions,quantity of frozen particle compositions administered, rate ofadministration of more than one frozen particle composition, spatiallocation for administration of one or more frozen particle compositions,temporal location for administration of one or more frozen particlecompositions, method of administration of one or more frozen particlecompositions, timing of administration of one or more frozen particlecompositions, modulation of administration of one or more frozenparticle compositions, deposition of one or more frozen particlecompositions, or rate of deposition of at least one agent.

In one embodiment, the at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions includes at least one parameter relating to at leastpartially ablating or at least partially abrading one or more surfacesof the at least one biological tissue with the one or more frozenparticle compositions. In one embodiment, the at least one parameter ofat least partially constructing or at least partially reconstructing theat least one biological tissue by administering one or more frozenparticle compositions includes at least one parameter relating toadministering at least one of a therapeutic agent, adhesive agent,biological remodeling agent, reinforcement agent, abrasive, or explosivematerial with the one or more frozen particle compositions. In oneembodiment, the spatial location for administration of one or morefrozen particle compositions includes one or more of x, y, or zcoordinates.

In one embodiment, the processing results includes comparing at leastone value related to the first input associated with the at least onecharacteristic of at least one biological tissue to be at leastpartially constructed or at least partially reconstructed with at leastone value related to at least one image of a target biological tissue.In one embodiment, the image of a target biological tissue includes animage of a similar biological tissue, or an image of a dissimilarbiological tissue. In one embodiment, administering one or more frozenparticle compositions includes depositing the at least one agent on theat least one substrate. In one embodiment, processing results includescomparing at least one value related to the second input associated withthe at least one parameter of at least partially constructing or atleast partially reconstructing the at least one biological tissue withat least one value related to another administration of one or morefrozen particle compositions.

In one embodiment, processing results includes determining one or moredifferences in at least one value related to the first input and atleast one value related to at least one image of the at least onebiological tissue or a similar biological tissue. In one embodiment,processing results includes determining one or more differences in atleast one value related to the second input associated with the at leastone parameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue and at least one valuerelated to another administration of one or more frozen particlecompositions to the at least one substrate. In one embodiment,processing results includes generating one or more protocols foradministering the one or more frozen particle compositions.

In one embodiment, processing results includes generating one or moreblueprints for administering the one or more frozen particlecompositions. In one embodiment, the one or more blueprints include atleast one of a two-dimesional plot or a three-dimensional model. In oneembodiment, the one or more blueprints include at least onerepresentation of at least one of organ anatomy, morphology, tissueheterogeneity, scale of vascular system, geometry, internal architectureof an organ or tissue, internal or external boundary distinction of atissue or organ, topology, or tomography.

In one embodiment, processing results includes: comparing one or morevalues related to the one or more characteristics of the at least onebiological tissue that are determined at two or more different times toobtain one or more characteristic comparisons; comparing one or morevalues related to the at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue at two or more different times to obtain one or moreparameter comparisons; comparing the one or more characteristiccomparisons with the one or more parameter comparisons to obtain one ormore characteristic-characteristic/parameter-parameter comparisons; andcomparing the one or morecharacteristic-characteristic/parameter-parameter comparisons to one ormore substantially similar results obtained for one or more other atleast partially constructed or at least partially reconstructedbiological tissues.

In one embodiment, the method further comprises displaying results ofthe processing. In one embodiment, displaying results of the processingincludes displaying the results on one or more active displays. In oneembodiment, displaying results of the processing includes displaying theresults on one or more passive displays. In one embodiment, displayingresults of the processing includes displaying the results of theprocessing in at least one of numeric format, graphical format, or audioformat. In one embodiment, displaying results of the processing includesdisplaying a comparison of at least one biological tissue that has beenat least partially constructed or at least partially reconstructed. Inone embodiment, displaying results of the processing includes displayinga comparison of at least one subject with one or more other subjects. Inone embodiment, displaying results of the processing includes displayingone or more differences in the comparison of at least one value relatedto the first input and at least one value related to at least one imageof a biological tissue.

In one embodiment, displaying results of the processing includesdisplaying one or more differences in the comparison of at least onevalue related to the second input and at least one value related toanother administration of one or more frozen particle compositions. Inone embodiment, the method further includes transmitting one or moresignals that include information related to the processing results ofthe first input and the second input. In one embodiment, transmittingone or more signals includes transmitting one or more signals associatedwith selection of one or more frozen particle compositions foradministration. In one embodiment, transmitting one or more signalsincludes transmitting one or more signals associated with selection ofone or more of a biological remodeling agent, adhesive agent, abrasive,therapeutic agent, reinforcement agent, or explosive material associatedwith the one or more frozen particle compositions. In one embodiment,transmitting one or more signals includes transmitting one or moresignals associated with comparing the information related to theprocessing results of the first input and the second input.

In one embodiment, the one or more frozen particle compositions includesone or more of an adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent.

In one embodiment, a method comprises accepting input associated with atleast one parameter of at least partially constructing or at leastpartially reconstructing the at least one biological tissue byadministering one or more frozen particle compositions; administeringone or more frozen particle compositions including at least one agentincluding a biological remodeling agent, therapeutic agent,reinforcement agent, explosive material, abrasive, or adhesive agent;evaluating the at least one biological tissue for one or more indicatorsrelated to deposition of at least one agent, tissue formation, or tissuegrowth; and transmitting one or more signals that include informationrelated to the accepting input and information related to the evaluatingthe at least one biological tissue.

In one embodiment, evaluating at least one biological tissue for one ormore indicators includes evaluating at least one of an assay, image, orgross assessment of the at least one biological tissue prior to, during,or subsequent to at least one administration of the one or more frozenparticle compositions. In one embodiment, the assay includes at leastone technique that includes spectroscopy, microscopy, electrochemicaldetection, polynucleotide detection, histological examination, biopsyanalysis, fluorescence resonance energy transfer, electron transfer,enzyme assay, electrical conductivity, isoelectric focusing,chromatography, immunoprecipitation, immunoseparation, aptamer binding,filtration, electrophoresis, immunoassay, or radioactive assay. In oneembodiment, the image includes at least one image acquired by one ormore of optical coherence tomography, computer-assisted tomography scan,computed tomography, magnetic resonance imaging, positron-emissiontomography scan, ultrasound, x-ray, electrical-impedance monitoring,microscopy, spectrometry, flow cytommetry, radioisotope imaging, thermalimaging, multiphoton calcium-imaging, photography, or in silicogeneration.

In one embodiment, one or more indicators of tissue formation or growthinclude at least one of cell migration, cell attachment, cell retention,cell differentiation, cell proliferation, apoptosis, diffusion ofmaterials, angiogenesis, nucleic acid expression, protein translation,protein modification, carbohydrate production, carbohydrate secretion,fat production, fat secretion, or protein secretion. In one embodiment,the input associated with at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions includes one or more of: constitution of the one or morefrozen particle compositions, formulation of the one or more frozenparticle compositions, size of the one or more frozen particlecompositions, shape of the one or more frozen particle compositions,angle of administration of the one or more frozen particle compositions,velocity of administration of the one or more frozen particlecompositions, quantity of frozen particle compositions administered,rate of administration of more than one frozen particle composition,spatial location for administration of one or more frozen particlecompositions, temporal location for administration of one or more frozenparticle compositions, method of administration of one or more frozenparticle compositions, timing of administration of one or more frozenparticle compositions, modulation of administration of one or morefrozen particle compositions, deposition of one or more frozen particlecompositions, or rate of deposition of at least one agent.

In one embodiment, transmitting one or more signals includestransmitting one or more signals associated with selection of one ormore frozen particle compositions for administration. In one embodiment,transmitting one or more signals includes transmitting one or moresignals associated with selection of one or more of a biologicalremodeling agent, adhesive agent, abrasive, therapeutic agent,reinforcement agent, or explosive material associated with the one ormore frozen particle compositions. In one embodiment, administering oneor more frozen particle compositions includes administering the one ormore frozen particle compositions to at least one substrate. In oneembodiment, at least one substrate includes one or more of a cell,tissue, organ, structure, or device.

In one embodiment, the one or more frozen particle compositions includesone or more of an adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent.

In one embodiment, a method comprises receiving one or more signals thatinclude information related to accepting input associated with at leastone parameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue by administering oneor more frozen particle compositions; receiving one or more signals thatinclude information related to evaluating the at least one biologicaltissue for one or more indicators of tissue formation or growth; andprocessing the information related to the input associated with at leastone parameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue and the informationrelated to the evaluating the at least one biological tissue.

In one embodiment, evaluating at least one biological tissue for one ormore indicators includes evaluating at least one of an assay, image, orgross assessment of the at least one biological tissue prior to, during,or subsequent to at least one administration of one or more frozenparticle compositions. In one embodiment, the assay includes at leastone technique that includes spectroscopy, microscopy, electrochemicaldetection, polynucleotide detection, histological examination, biopsyanalysis, fluorescence resonance energy transfer, electron transfer,enzyme assay, electrical conductivity, isoelectric focusing,chromatography, immunoprecipitation, immunoseparation, aptamer binding,filtration, electrophoresis, immunoassay, or radioactive assay.

In one embodiment, the image includes at least one image acquired by oneor more of optical coherence tomography, computer-assisted tomographyscan, computed tomography, magnetic resonance imaging, positron-emissiontomography scan, ultrasound, x-ray, electrical-impedance monitoring,microscopy, spectrometry, flow cytommetry, radioisotope imaging, thermalimaging, multiphoton calcium-imaging, photography, or in silicogeneration. In one embodiment, one or more indicators of tissueformation or growth include at least one of: cell migration, cellattachment, cell retention, cell differentiation, cell proliferation,apoptosis, diffusion of materials, angiogenesis, nucleic acidexpression, protein translation, protein modification, carbohydrateproduction, carbohydrate secretion, fat production, fat secretion, orprotein secretion.

In one embodiment, the input associated with at least one parameter ofat least partially constructing or at least partially reconstructing theat least one biological tissue includes one or more of: constitution ofthe one or more frozen particle compositions, formulation of the one ormore frozen particle compositions, size of the one or more frozenparticle compositions, shape of the one or more frozen particlecompositions, angle of administration of the one or more frozen particlecompositions, velocity of administration of the one or more frozenparticle compositions, quantity of frozen particle compositionsadministered, rate of administration of more than one frozen particlecomposition, spatial location for administration of one or more frozenparticle compositions, temporal location for administration of one ormore frozen particle compositions, method of administration of one ormore frozen particle compositions, timing of administration of one ormore frozen particle compositions, modulation of administration of oneor more frozen particle compositions, deposition of one or more frozenparticle compositions, or rate of deposition of at least one agent.

In one embodiment, receiving one or more signals includes receiving oneor more signals associated with selection of one or more frozen particlecompositions for administration. In one embodiment, receiving one ormore signals includes receiving one or more signals associated with theselection of at least one of a biological remodeling agent, adhesiveagent, abrasive, therapeutic agent, reinforcement agent, or explosivematerial associated with the one or more frozen particle compositions.

In one embodiment, administering one or more frozen particlecompositions includes administering the one or more frozen particlecompositions to at least one substrate. In one embodiment, the at leastone substrate includes one or more of a cell, tissue, organ, structure,or device. In one embodiment, the one or more frozen particlecompositions includes one or more of an adhesive agent, therapeuticagent, reinforcement agent, abrasive, explosive material, or biologicalremodeling agent.

In one embodiment, a method comprises comparing information regarding atleast one parameter for at least partially constructing or at leastpartially reconstructing at least one biological tissue of a subject byadministering one or more frozen particle compositions to the at leastone subject and information regarding at least one clinical outcomefollowing receipt by the at least one subject of one or more frozenparticle compositions; and providing output information.

In one embodiment, the output information is based on the comparison. Inone embodiment, the method further comprises determining at least onestatistical correlation. In one embodiment, the method further comprisescounting the occurrence of at least one clinical outcome. In oneembodiment, the information regarding at least one parameter of at leastpartially constructing or at least partially reconstructing at least onebiological tissue of a subject includes information regarding quantityof cells or tissue at least partially constructed or at least partiallyreconstructed. In one embodiment, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of a subject includesinformation regarding at least one cellular or tissue source.

In one embodiment, the information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of a subject includes information regardingat least one abnormal cellular or tissue source. In one embodiment, theinformation regarding at least one parameter of at least partiallyconstructing or at least partially reconstructing at least onebiological tissue of a subject includes information regarding at leastone type of cell or tissue. In one embodiment, the one or more frozenparticle compositions includes at least one agent including at least oneadhesive agent, abrasive, reinforcement agent, therapeutic agent,biological remodeling agent, or explosive material.

In one embodiment, the information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of a subject includes information regardingat least one dimension of at least one agent deposited. In oneembodiment, the information regarding at least one parameter of at leastpartially constructing or at least partially reconstructing at least onebiological tissue of at least one subject includes information regardingat least one dimension of at least one depth, width, or breadth ofcellular, tissue, or other material removal or destruction.

In one embodiment, the information regarding at least one clinicaloutcome following receipt by the at least one subject of one or morefrozen particle compositions includes information regarding two or moresubjects with one or more common attributes. In one embodiment, the oneor more common attributes include one or more of genetic attributes,mental attributes, proteomic attributes, phenotypic attributes, orpsychological attributes. In one embodiment, the one or more commonattributes include one or more of height, weight, medical diagnosis,familial background, results on one or more medical tests, ethnicbackground, body mass index, age, presence or absence of at least onedisease or condition, species, ethnicity, race, allergies, gender,thickness of tissue, blood vessel condition, hair or fur condition, skincondition, tissue condition, muscle condition, organ condition, nervecondition, brain condition, presence or absence of at least onebiological, chemical, or therapeutic agent in the subject, pregnancystatus, lactation status, genetic profile, proteomic profile, partial orwhole genetic sequence, partial or whole proteomic sequence, medicalcondition, medical history, or blood condition.

In one embodiment, the output information includes at least one of aresponse signal, comparison code, comparison plot, diagnostic code,treatment code, test code, code indicative of at least one treatmentreceived, code indicative of at least one prescribed treatment step,code indicative of at least one vaccination administered, codeindicative of at least one therapeutic agent administered, codeindicative of at least one diagnostic agent administered, codeindicative of at least one interaction of an administered agent and atleast one biological or chemical agent in the subject; a code indicativeof at least one dispertion or location of at least one administeredagent; code indicative of at least one detection material administered;code indicative of the depth of penetration of an administered agent,code indicative of the depth of deposition of an administered agent, ora code indicative of the condition of at least one location of anadministered frozen particle composition.

In one embodiment, receipt by the at least one subject of one or morefrozen particle compositions is pursuant to at least one clinical trial.In one embodiment, the method further comprises determining at least onecorrelation before the administration of the one or more frozen particlecompositions to the at least one subject. In one embodiment, the methodfurther comprises creating at least one inclusion criterion and at leastone exclusion criterion for a clinical trial involving the one or morefrozen particle compositions. In one embodiment, the method furthercomprises suggesting the inclusion of one or more of the at least onesubject in at least one clinical trial. In one embodiment, the methodfurther comprises suggesting the exclusion of one or more of the atleast one subject in at least one clinical trial. In one embodiment, themethod further comprises using one or more of the at least onecorrelation to predict at least one clinical outcome regarding at leastone second subject.

In one embodiment, the at least one second subject has not received theone or more frozen particle compositions. In one embodiment, the methodfurther comprises predicting at least one clinical outcome involving theat least one second subject, wherein the at least one second subject isa plurality of people; and segregating subject identifiers associatedwith the plurality of people in reference to the predicted at least oneclinical outcome. In one embodiment, the method further comprisesdetermining the eligibility of the at least one second subject for theat least one clinical trial.

In one embodiment, the one or more frozen particle compositions includesone or more of an adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent.

In one embodiment, a method of predicting a clinical outcome of one ormore frozen particle compositions treatment for at least one firstsubject, comprises: determining a similarity or a dissimilarity ininformation regarding at least one parameter for at least partiallyconstructing or at least partially reconstructing at least onebiological tissue of at least one first subject by administering one ormore frozen particle compositions to the at least one first subject withinformation regarding at least one parameter of at least partiallyconstructing or at least partially reconstructing at least onebiological tissue of at least one second subject, wherein the at leastone second subject attained a clinical outcome following receipt of oneor more frozen particle compositions; and providing output information.In one embodiment, providing output information is based on thedetermination. In one embodiment, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least second subjectincludes information regarding quantity of cells or tissue at leastpartially constructed or at least partially reconstructed.

In one embodiment, the information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of at least one first subject includesinformation regarding at least one cellular or tissue source. In oneembodiment, the information regarding at least one parameter of at leastpartially constructing or at least partially reconstructing at least onebiological tissue of at least one first subject includes informationregarding at least one abnormal cellular or tissue source. In oneembodiment, the information regarding at least one parameter of at leastpartially constructing or at least partially reconstructing at least onebiological tissue of at least one first subject includes informationregarding at least one type of cell or tissue.

In one embodiment, the information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of at least one second subject includesinformation regarding at least one type of cell or tissue.

In one embodiment, the one or more frozen particle compositions includesat least one agent including at least one adhesive agent, abrasive,reinforcement agent, therapeutic agent, biological remodeling agent, orexplosive material. In one embodiment, the information regarding atleast one parameter of at least partially constructing or at leastpartially reconstructing at least one biological tissue of at least onefirst subject includes information regarding at least one dimension ofat least one agent deposited. In one embodiment, the informationregarding at least one parameter of at least partially constructing orat least partially reconstructing at least one biological tissue of atleast one second subject includes information regarding at least onedimension of at least one agent deposited.

In one embodiment, the information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of at least one second subject includesinformation regarding at least one dimension of at least one depth,width, or breadth of cellular, tissue, or other material removal ordestruction. In one embodiment, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least one firstsubject includes information regarding at least one dimension of atleast one depth, width, or breadth of cellular, tissue, or othermaterial removal or destruction. In one embodiment, the informationregarding at least one clinical outcome following receipt by the atleast one second subject of one or more frozen particle compositionsincludes information regarding two or more subjects with one or morecommon attributes. In one embodiment, the one or more common attributesinclude one or more of genetic attributes, mental attributes, proteomicattributes, phenotypic attributes, or psychological attributes.

In one embodiment, the one or more common attributes include one or moreof height, weight, medical diagnosis, familial background, results onone or more medical tests, ethnic background, body mass index, age,presence or absence of at least one disease or condition, species,ethnicity, race, allergies, gender, thickness of tissue, blood vesselcondition, hair or fur condition, skin condition, tissue condition,muscle condition, organ condition, nerve condition, brain condition,presence or absence of at least one biological, chemical, or therapeuticagent in the subject, pregnancy status, lactation status, geneticprofile, proteomic profile, partial or whole genetic sequence, partialor whole proteomic sequence, medical condition, medical history, orblood condition.

In one embodiment, the output information includes at least one of aresponse signal, comparison code, comparison plot, diagnostic code,treatment code, test code, code indicative of at least one treatmentreceived, code indicative of at least one prescribed treatment step,code indicative of at least one vaccination administered, codeindicative of at least one therapeutic agent administered, codeindicative of at least one diagnostic agent administered, codeindicative of at least one interaction of an administered agent and atleast one biological or chemical agent in the subject; a code indicativeof at least one dispertion or location of at least one administeredagent; code indicative of at least one detection material administered;code indicative of the depth of penetration of an administered agent,code indicative of the depth of deposition of an administered agent, ora code indicative of the condition of at least one location of anadministered frozen particle composition.

In one embodiment, receipt by the at least one second subject of one ormore frozen particle compositions is pursuant to at least one clinicaltrial. In one embodiment, the method further comprises determining atleast one correlation before the administration of the one or morefrozen particle compositions to the at least one first subject. In oneembodiment, the method further comprises creating at least one inclusioncriterion and at least one exclusion criterion for a clinical trialinvolving the one or more frozen particle compositions. In oneembodiment, the method further comprises suggesting the inclusion of oneor more of the at least one first subject in at least one clinicaltrial.

In one embodiment, the method further comprises suggesting the exclusionof one or more of the at least one first subject in at least oneclinical trial. In one embodiment, the method further comprises usingone or more of the at least one correlation to predict at least oneclinical outcome regarding at least one second subject. In oneembodiment, the at least one second subject has not received the one ormore frozen particle compositions. In one embodiment, the method furthercomprises predicting at least one clinical outcome involving the atleast one second subject, wherein the at least one second subject is aplurality of people; and segregating subject identifiers associated withthe plurality of people in reference to the predicted at least oneclinical outcome.

In one embodiment, the one or more frozen particle compositions includesone or more of an adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent. Inone embodiment, the at least one biological remodeling agent is includedas part of a carrier that assists in synthesis or activation of the atleast one biological remodeling agent.

In one embodiment, a system comprises: at least one computing device;one or more instructions that when executed on the at least onecomputing device cause the at least one computing device to receive afirst input associated with a first possible dataset, the first possibledataset including data representative of one or more parameters foradministering one or more frozen particle compositions. In oneembodiment, the system further comprises one or more instructions thatwhen executed on the at least one computing device cause the at leastone computing device to compare a value associated with the firstpossible dataset with a second dataset including values of at least onepredictive parameter for administering one or more frozen particlecompositions.

In one embodiment, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to determine from the comparison at least oneparameter for administering one or more frozen particle compositions. Inone embodiment, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to generate at least one response based onthe determination. In one embodiment, the system further comprises oneor more instructions that when executed on the at least one computingdevice cause the at least one computing device to access the firstpossible dataset in response to the first input. In one embodiment, thesystem further comprises one or more instructions that when executed onthe at least one computing device cause the at least one computingdevice to generate the first possible dataset in response to the firstinput.

In one embodiment, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to determine a graphical illustration of thefirst possible dataset. In one embodiment, the system further comprisesone or more instructions that when executed on the at least onecomputing device cause the at least one computing device to determine agraphical illustration of the second possible dataset. In oneembodiment, the at least one computing device includes one or more of adesktop computer, workstation computer, or computing system. In oneembodiment, the at least one computing system includes one or more of acluster of processors, a networked computer, a tablet personal computer,a laptop computer, a mobile device, a mobile telephone, or a personaldigital assistant computer.

In one embodiment, a system comprises at least one computing device; oneor more instructions that when executed on the at least one computingdevice cause the at least one computing device to receive a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of one or more characteristics of at leastone biological tissue or organ to be at least partially constructed orat least partially reconstructed by administering one or more frozenparticle compositions.

In one embodiment, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to compare a value associated with the firstpossible dataset with a second dataset including values of at least onepredictive characteristic of at least one biological tissue to be atleast partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions.

In one embodiment, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to determine from the comparison at least onecharacteristic of the at least one biological tissue or organ to be atleast partially constructed or at least partially reconstructed. In oneembodiment, the system further comprises one or more instructions thatwhen executed on the at least one computing device cause the at leastone computing device to generate at least one response based on thedetermination. In one embodiment, the system further comprises one ormore instructions that when executed on the at least one computingdevice cause the at least one computing device to access the firstpossible dataset in response to the first input. In one embodiment, thesystem further comprises one or more instructions that when executed onthe at least one computing device cause the at least one computingdevice to generate the first possible dataset in response to the firstinput. In one embodiment, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to determine a graphicalillustration of the first possible dataset. In one embodiment, thesystem further comprises one or more instructions that when executed onthe at least one computing device cause the at least one computingdevice to determine a graphical illustration of the second possibledataset.

In one embodiment, the at least one computing device includes one ormore of a desktop computer, workstation computer, or computing system.In one embodiment, at least one computing system includes one or more ofa cluster of processors, a networked computer, a tablet personalcomputer, a laptop computer, a mobile device, a mobile telephone, or apersonal digital assistant computer. In one embodiment, the at least onecomputing device is configured to communicate with at least oneapparatus for selecting or generating one or more frozen particlecompositions.

In one embodiment, a system comprises: a signal-bearing medium bearingone or more instructions for accepting a first input associated with atleast one characteristic of at least one biological tissue to be atleast partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions; one or moreinstructions for accepting a second input associated with at least onecharacteristic of at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions that include at least one agent; and one or moreinstructions for processing results of the first input and the secondinput. In one embodiment, the signal-bearing medium includes acomputer-readable medium. In one embodiment, the signal-bearing mediumincludes a recordable medium. In one embodiment, the signal-bearingmedium includes a communications medium.

In one embodiment, the system further comprises one or more instructionsfor displaying results of the processing. In one embodiment, the systemfurther comprises one or more instructions for transmitting one or moresignals that include information related to the processing results ofthe first input and the second input. In one embodiment, the systemfurther comprises one or more instructions for administering one or morefrozen particle compositions that include at least one agent including:biological remodeling agent, therapeutic agent, adhesive agent,abrasive, reinforcement agent, or explosive material. In one embodiment,the system further comprises one or more instructions for evaluating theat least one biological tissue for one or more indicators relating toone or more of: deposition of at least one agent, tissue formation, ortissue growth.

In one embodiment, a system comprises circuitry for accepting a firstinput associated with at least one characteristic of at least onebiological tissue to be at least partially constructed or at leastpartially reconstructed by administering one or more frozen particlecompositions; circuitry for accepting a second input associated with atleast one characteristic of at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions that include at least one agent; and circuitry forprocessing results of the first input and the second input. In oneembodiment, the system further comprises circuitry for displayingresults of the processing. In one embodiment, the system furthercomprises circuitry for transmitting one or more signals that includeinformation related to the processing results of the first input and thesecond input. In one embodiment, the system further comprises circuitryfor administering one or more frozen particle compositions that includeat least one agent including at least one biological remodeling agent,therapeutic agent, adhesive agent, abrasive, reinforcement agent, orexplosive material. In one embodiment, the system further comprisescircuitry for evaluating the at least one biological tissue for one ormore indicators relating to one or more of deposition of at least oneagent, tissue formation, or tissue growth.

In one embodiment, a computer program product comprises: asignal-bearing medium bearing one or more instructions for accepting afirst input associated with at least one characteristic of at least onebiological tissue to be at least partially constructed or at leastpartially reconstructed by administering one or more frozen particlecompositions; one or more instructions for accepting a second inputassociated with at least one characteristic of at least one parameter ofat least partially constructing or at least partially reconstructing theat least one biological tissue by administering one or more frozenparticle compositions that include at least one agent; and one or moreinstructions for processing results of the first input and the secondinput. In one embodiment, the signal-bearing medium includes acomputer-readable medium. In one embodiment, the signal-bearing mediumincludes a recordable medium. In one embodiment, the signal-bearingmedium includes a communications medium. In one embodiment, the computerprogram product further comprises one or more instructions fordisplaying results of the processing. In one embodiment, the computerprogram product further comprises one or more instructions fortransmitting one or more signals that include information related to theprocessing results of the first input and the second input.

In one embodiment, the computer program product further comprises one ormore instructions for administering one or more frozen particlecompositions that include at least one agent including: biologicalremodeling agent, therapeutic agent, adhesive agent, abrasive,reinforcement agent, or explosive material. In one embodiment, thecomputer program product further comprises one or more instructions forevaluating the at least one biological tissue for one or more indicatorsrelating to one or more of: deposition of at least one agent, tissueformation, or tissue growth.

In one embodiment, a system comprises: a signal-bearing medium bearingone or more instructions for accepting a first input associated with atleast one characteristic of at least one biological tissue to be atleast partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions; one or moreinstructions for accepting a second input associated with at least onecharacteristic of at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions that include at least one agent; and one or moreinstructions for processing results of the first input and the secondinput. In one embodiment, the signal-bearing medium includes acomputer-readable medium. In one embodiment, the signal-bearing mediumincludes a recordable medium. In one embodiment, the signal-bearingmedium includes a communications medium. In one embodiment, the systemfurther comprises one or more instructions for displaying results of theprocessing. In one embodiment, the system further comprises one or moreinstructions for transmitting one or more signals that includeinformation related to the processing results of the first input and thesecond input.

In one embodiment, the system further comprises one or more instructionsfor administering one or more frozen particle compositions that includeat least one agent including: biological remodeling agent, therapeuticagent, adhesive agent, abrasive, reinforcement agent, or explosivematerial. In one embodiment, the system further comprises one or moreinstructions for evaluating the at least one biological tissue for oneor more indicators relating to one or more of: deposition of at leastone agent, tissue formation, or tissue growth.

In one embodiment, a system comprises: at least one computer program,configured with a computer-readable medium, for use with at least onecomputer system and wherein the computer program includes a plurality ofinstructions including but not limited to: one or more instructions foraccepting a first input associated with at least one characteristic ofat least one biological tissue to be at least partially constructed orat least partially reconstructed by administering one or more frozenparticle compositions; one or more instructions for accepting a secondinput associated with at least one characteristic of at least oneparameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue by administering oneor more frozen particle compositions that include at least one agent;and one or more instructions for processing results of the first inputand the second input. In one embodiment, the system further comprisesone or more instructions for displaying results of the processing. Inone embodiment, the system further comprises one or more instructionsfor transmitting one or more signals that include information related tothe processing results of the first input and the second input.

In one embodiment, the system further comprises one or more instructionsfor administering one or more frozen particle compositions that includeat least one agent including: biological remodeling agent, therapeuticagent, adhesive agent, abrasive, reinforcement agent, or explosivematerial. In one embodiment, the system further comprises one or moreinstructions for evaluating the at least one biological tissue for oneor more indicators relating to one or more of: deposition of at leastone agent, tissue formation, or tissue growth. In one embodiment, the atleast one computer system includes at least one computing device. In oneembodiment, the at least one computing device is configured tocommunicate with at least one printing device, at least one imagingdevice, or at least one input device.

In one embodiment, a computer program product comprises: asignal-bearing medium bearing one or more instructions for accepting afirst input associated with at least one characteristic of at least onebiological tissue to be at least partially constructed or at leastpartially reconstructed by administering one or more frozen particlecompositions; one or more instructions for accepting a second inputassociated with at least one characteristic of at least one parameter ofat least partially constructing or at least partially reconstructing theat least one biological tissue by administering one or more frozenparticle compositions including at least one agent; and one or moreinstructions for processing results of the first input and the secondinput.

In one embodiment, the signal-bearing medium includes acomputer-readable medium. In one embodiment, the signal-bearing mediumincludes a recordable medium. In one embodiment, the signal-bearingmedium includes a communications medium. In one embodiment, the computerprogram product further comprises one or more instructions fordisplaying results of the processing. In one embodiment, the computerprogram product further comprises one or more instructions fortransmitting one or more signals that include information related to theprocessing results of the first input and the second input. In oneembodiment, the computer program product further comprises one or moreinstructions for administering one or more frozen particle compositionsthat include at least one agent including: biological remodeling agent,therapeutic agent, adhesive agent, abrasive, reinforcement agent, orexplosive material. In one embodiment, the computer program productfurther comprises one or more instructions for evaluating the at leastone biological tissue for one or more indicators relating to one or moreof: deposition of at least one agent, tissue formation, or tissuegrowth.

As described herein, at least one frozen particle composition ortherapeutic composition described herein is useful in one or moremethods, including one or more of a method for abrasion of at least onebiological tissue surface of a subject by delivering at least onecomposition to at least one surface of at least one biological tissue ofa subject in a manner sufficient to abrade the at least one surface ofthe at least one biological tissue; a method of delivering at least onetherapeutic agent to at least one biological tissue; a method ofvaccinating a subject; a method of treating a tissue related totransplantation; a method for cleaning one or more wounds; a method fordebridement of tissue or cells; a method for removing material from oneor more blood vessel, and others. These and other methods includeutilizing one or more composition or therapeutic composition describedherein.

In one embodiment, a method of providing at least one agent to at leastone biological tissue of a subject comprises administering at least onefrozen particle composition to at least one biological tissue, whereinthe at least one frozen particle composition includes one or more frozenparticles defining at least one cavity and at least one agent; and theat least one cavity containing at least one agent.

In one embodiment, a method of vaccinating a subject comprisesadministering to at least one biological tissue of a subject at leastone frozen particle composition, wherein the at least one frozenparticle composition includes one or more frozen particles defining atleast one cavity; the at least one cavity containing at least onevaccine. In one embodiment, a method of vaccinating at least onesubstrate, such as a biological tissue, includes administering to thesubstrate at least one frozen particle composition, wherein the at leastone frozen particle composition includes one or more frozen particlesdefining at least one cavity; the at least one cavity containing atleast one vaccine.

In one embodiment, a method of providing at least one frozen particlecomposition to at least one biological tissue of a subject comprisesadministering at least one frozen particle composition to at least onebiological tissue, wherein the at least one frozen particle compositionincludes one or more frozen particles including at least one cavityconfigured for holding at least one agent.

In one embodiment, a method for abrasion of at least one biologicaltissue surface of a subject includes delivering at least one compositionto at least one surface of at least one biological tissue of a subjectin a manner sufficient to abrade the at least one surface of the atleast one biological tissue. As discussed herein, particular methods aredisclosed for abrading or ablating at least one surface of at least onebiological tissue.

In one particular example, skin abrasion for superficial resurfacing(e.g., microdermabrasion) can be used to treat acne, scars,hyperpigmentation, and other skin blemishes, as described herein.Microscissuining creates microchannels in the skin by eroding the outerlayers of skin with sharp microscopic metal granules (CarlisleScientific, Carlisle, Mass.), and Med Pharm Ltd (Charlbury, UK) hasdeveloped a novel dermal abrasion device (D3S) for the delivery ofdifficult to formulate therapeutics ranging from hydrophilic lowmolecular weight compounds to other biopharmaceuticals, and can beutilized in conjunction with administration of at least one compositiondescribed herein. (See e.g., Roberts, et al., Clin. Exp. Pharmacol.Physiol. vol. 24, pp. 874-9 (1997); Murthy, et al., J. Controlled Rel.vol. 93, pp. 49-57 (2003); each of which is incorporated herein byreference).

Abrading at least one surface of at least one biological tissue mayentail debridement of at least one biological tissue. In certaininstances, debridement may include removal or destruction of dead,damaged, or infected cells or tissues. In certain instances, debridementcan be included as part of an additional course of treatment (e.g.,surgery). In one embodiment, debridement may include penetrating one ormore healthy cells or tissues in order to facilitate healing. In oneembodiment, debridement may include penetrating one or more healthycells or tissues near in proximity to one or more unhealthy cells ortissues of a subject.

In one embodiment, one or more of the debridement methods describedherein include penetrating one or more cells or biological tissues of asubject with at least one frozen particle composition or therapeuticcomposition, wherein the one or more cells or tissues are chemically orphysically partitioned or segregated from at least one other part of thetissue or another tissue. In one embodiment, a method for debridement ofat least one biological tissue of a subject includes delivering at leastone frozen particle composition or therapeutic composition to at leastone biological tissue of a subject wherein the at least one biologicaltissue is partitioned from another biological tissue or part of anotherbiological tissue, and at least one frozen particle composition ortherapeutic composition penetrates the at last one biological tissuewith or without removing any tissue. In certain instances, a therapeuticagent is included with the at least one frozen particle composition ortherapeutic composition, as described herein. In certain instances, oneor more reinforcement agents or one or more explosive materials can beincluded in the at least one frozen particle composition or therapeuticcomposition.

In one embodiment, a method for removing one or more materials from atleast one biological tissue includes delivering or administering atleast one frozen particle composition or therapeutic composition to theat least one biological tissue. In one embodiment, the at least onebiological tissue includes one or more tissues described herein. In oneembodiment, the one or more materials may include one or more materialsdescribed herein.

In one embodiment, a method for removing one or more materials from atleast one blood vessel of at least one subject includes delivering atleast one composition to at least one blood vessel of a subject in amanner sufficient to remove one or more materials.

In certain instances, a method for abrasion of at least one biologicaltissue or organ surface related to transplantation is included. In oneembodiment, the at least one biological tissue or organ includes one ormore of the biological tissues or organs described herein.

In one embodiment, delivering at least one composition to at least onesurface of at least one biological tissue of a subject includescontacting the at least one surface of at least one biological tissue ofa subject with the composition. In one embodiment, delivering at leastone composition to at least one surface of at least one biologicaltissue of a subject includes contacting the at least one surface of atleast one biological tissue of a subject with the one or more frozenparticle compositions. In one embodiment, delivering at least onecomposition to at least one surface of at least one biological tissue ofa subject includes rupturing one or more cells of at least one surfaceof at least one biological tissue of a subject with the one or morefrozen particle compositions.

In one embodiment, a method described herein includes extracting orcollecting material from the at least one abraded surface of at leastone biological tissue. Such extraction or collection may include the useof at least one vacuum, aspirator, container, instrument, tool, device,chemical, laser, stylet, cannula, light source, scope (e.g.,laprascope), needle, scalpel, shunt, stent, bag, film, filter, suctionapparatus, tube, compressed gas, fluid (e.g., fluid stream or mist),magnifying apparatus, imaging device, computing device, or system.

In one embodiment, at least one of the needle, scalpel, or other toolsor instruments utilized in extracting or collecting material from the atleast one cell, tissue, or subject, includes one or more frozen particlecompositions (e.g., frozen hydrogen oxide, or other agents as describedherein). Thus, the one or more frozen particle compositions arefashioned or molded for use as microneedles or other instruments (e.g.,scapels, blades, tools, etc.). In one embodiment, the one or more frozenparticle compositions are administered prior to, during, or subsequentto surgery.

In one embodiment, the extracted or collected material includes at leastone organic or inorganic material. In one embodiment, the materialincludes one or more cells from the at least one abraded surface of atleast one biological tissue. In one embodiment, the at least onematerial includes at least part of one or more granuloma, eschar,callus, atheromatous plaque, abscess, pustule, scaling (e.g., psoriasisor eczema), infected tissue, microorganism accumulation, blood clot,blood vessel obstruction, duct obstruction, bowel obstruction, necrotictissue, stratum corneum, hair follicle, nevus, wrinkle, keloid, biofilm,calculus, plaque, tartar, dandruff, keratin, collagen, dust, dirt,metal, glass, hair or fur, cellular secretion, microorganism, bloodcell, particulate matter, or connective tissue.

As indicated herein, in one embodiment, a method for providing at leastone therapeutic agent to at least one biological tissue of a subject isincluded. In one embodiment, the at least one therapeutic agent isdelivered to at least one biological tissue prior to, during, orsubsequent to surgery. In certain instances, at least one therapeuticagent includes one or more therapeutic agents described herein. In oneembodiment, a method of providing at least one therapeutic agent to atleast one biological tissue of a subject includes delivering at leastone composition to at least one biological tissue, including one or morefrozen hydrogen oxide particles including at least one therapeuticagent; wherein the at least one composition has at least one crystallineor amorphous phase.

In certain aspects, a method relates to vaccinating a subject byadministering at least one composition that includes at least onevaccine. The composition can be administered singularly, or inconjunction with another treatment, such as surface abrasion therapy. Inone embodiment, a method of vaccinating a subject includes administeringto a subject at least one composition; wherein the at least onecomposition includes one or more frozen hydrogen oxide particles, and atleast one vaccine; wherein the composition has at least one crystallineor amorphous phase.

In one embodiment, a method of vaccinating a subject includesadministering to a subject at least one composition described herein. Inan embodiment, the at least one composition includes one or more frozenparticles, including at least one of air, oxygen, nitrogen, carbondioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, argon, polyethylene glycol, acetone, ethyl acetate,dimethyl sulfoxide, dimethyl formamide, dioxane,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, aceticacid, benzene, carbon tetrachloride, acetonitrile, hexane, methylenechloride, carboxylic acid, saline, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, or diethyl ether; and at leastone vaccine.

As disclosed herein for other embodiments, a method of vaccinating asubject includes administering at least one composition that includes atleast one vaccine, as well as one or more abrasives, one or morereinforcement agents, or one or more explosive materials. In oneembodiment, the vaccine described herein relates to a therapeutic orprophylactic vaccine, and in certain instances the vaccine relates to ananti-cancer vaccine. In one embodiment, the one or more abrasives arethe same as the one or more reinforcement agents, or the one or moreexplosive materials. In one embodiment, the one or more abrasives aredifferent than the one or more reinforcement agents. In one embodiment,the one or more abrasives are different than the one or more explosivematerials.

In certain instances, for example with at least one vaccine compositionor method relate to vaccinating wildlife animals (e.g. vaccinatingraccoons for rabies, or bison for brucellosis). In certain instances,the vaccine compositions and methods described herein relate tovaccinating domesticated animals (such as cattle, horses, sheep, orgoats). In certain instances, vaccine compositions and methods describedherein relate to vaccinating a group of subjects, such as a population,a herd, a pride, a gaggle, a pack, flock, band, cluster, school, brood,troop, colony, or other group. In certain instances, vaccinating a groupof subjects is included as a route to regulate or control infectionwithin a group of subjects.

In one embodiment, the one or more frozen particle compositions aredelivered or administered to the at least one substrate, such as atleast one biological tissue, in a directed manner such that the tissueis etched, tattooed, shaped, carved, or otherwise modified. In oneembodiment, the directed manner is predetermined based on information,such as from the at least one biological tissue, the subject, the atleast one frozen particle composition, the context of the debridement,the health of the biological tissue, the health of the subject, or otherinformation.

Devices

In one embodiment, one or more methods, devices, or systems describedherein include making or administering one or more frozen particlecompositions. In one embodiment, frozen particle compositions asdescribed herein are made by one or more processes.

In one embodiment, at least one first fluid composition is contactedwith at least one second fluid for a time and condition sufficient toform one or more frozen particle compositions as described herein.

In one embodiment, at least one agent (e.g., a reinforcement agent) isutilized to freeze with one or more components, or substances. In oneembodiment, the at least one agent is a solid, and at least onesubstance or component is a liquid. The mixture or solution is frozen,and frozen particle compositions are generated as described herein.

In one embodiment, one or more frozen particle compositions are extrudedby way of a die, or molding. In one embodiment, one or more frozenparticle compositions are generated with assistance of at least onerefrigerant or cryogen, including but not limited to liquid nitrogen.

In one embodiment, at least one agent (e.g., a reinforcement agent) isutilized to crystallize one or more components or substances. Thecrystallization is frozen, and frozen particle compositions aregenerated as described herein.

In one embodiment, one or more methods, devices, or systems describedherein include delivering or administering one or more frozen particlecompositions by high velocity impact. In one embodiment, the one or moredevices that utilize high velocity impact delivery provide at least oneof localized delivery, targeted delivery, sustained delivery, modulateddelivery, feedback controlled delivery. In some instances, an example ofa device that can be used for administering one or more of thecompositions described herein includes a handheld device, such as awand, a pen, a baton, a hose, a sprayer, a gun (e.g., a particle orpellet gun), or other handheld device. In certain instances, the deviceis at least part of a built-in delivery device, such as can be includedin a wall, an overhead device, a corral, a gate, or a device thatincludes a cavity into which a subject can be placed for administrationor delivery of at least one composition described herein. In certaininstances, the device has robotic action. In any of these instances, thedevice can be remotely controlled, for example, by a human, computersystem, or computer program.

In one embodiment, the device includes at least one nozzle, such as aventuri nozzle, de Laval nozzle, or virtual Laval nozzle. See, forexample, U.S. Pat. Nos. 4,038,786; 4,707,951; and 5,779,523, each ofwhich is incorporated herein by reference. In one embodiment, the deviceincludes at least one amplifier to increase the flow or passage of theone or more frozen particle compositions through or out of the device.See, for example, U.S. Pat. No. 4,398,820, which is incorporated hereinby reference. In one embodiment, the device includes at least oneinjector, such as an oblique injector, that allows for introduction of afluid (e.g., a gas or liquid) to assist in moving the one or more frozenparticle compositions through or out of the device. (See, for example,U.S. Pat. No. 4,555,872, which is incorporated herein by reference.)

In one embodiment, the one or more frozen particle compositions are madeby freezing all or some of the particular components for thecomposition. Next, the frozen composition is extruded through orificesin a die and are either sliced during extrusion, ground down, orotherwise manipulated to form the frozen particle compositions describedherein.

In one embodiment, administering or delivering the at least one frozenparticle composition includes at least one of accelerating, ejecting, orpropelling the frozen particle composition. In one embodiment, themethod for administering at least one frozen particle compositionincludes at least one of accelerating, ejecting, or propelling thefrozen particle composition toward at least one substrate. In oneembodiment, the at least one frozen particle composition is accelerated,ejected, or propelled to or at a predetermined pressure or velocity fordelivery of the at least one composition to a desired location on or inthe at least one substrate (such as a biological tissue). In certaininstances, the at least one frozen particle composition is accelerated,ejected, or propelled at a particular pressure, angle, or velocity. Incertain instances, the at least one frozen particle composition isaccelerated, ejected, or propelled at a predetermined pressure, angle,or velocity.

The angle, velocity or pressure determined for delivery of the at leastone frozen particle composition depends on certain factors, includingbut not limited to, size and density of the frozen particle composition,content of the frozen particle composition, desired effect or outcome ofadministration of the frozen particle composition, density of the targettissue, density of surrounding tissue, type of tissue, architecture ofthe tissue, and other factors. In certain instances, the desired angle,velocity or pressure for accelerating, ejecting, or propelling the atleast one frozen particle composition described herein will be theminimum angle, velocity or pressure needed to achieve desiredpenetration of the substrate (including a biological tissue) with thefrozen particle composition, whether for surface abrasion, therapeuticdelivery, or other goal.

In addition to the angle and velocity of accelerating, ejecting, orpropelling the at least one composition, other factors affect the depthof penetration of a particular composition, including one or morecharacteristics of the particular composition (e.g., size, shape, orconstitution of the frozen particle composition) or one or morecharacteristics of administration of the particular composition (e.g.,the quantity of frozen particle compositions administered, distancebetween the delivery device and the target substrate).

The means for accelerating, ejecting, or propelling the one or morefrozen particle compositions described herein are non-limiting, and mayinclude general methods for making, formulating, and delivering the oneor more frozen particle compositions. For example, the one or morefrozen particle compositions may be delivered to at least one substrate(such as a biological tissue) by carrier gas under pressure, mechanicalor electrical impulse assistance, centripetal or centrifugal force, orothers, some of which are described herein. (See e.g., U.S. Pat. No.4,945,050 and PCT application WO 92/01802, each of which is incorporatedherein by reference). In certain instances, the one or more frozenparticle compositions are made, propelled, accelerated, or ejectedsimultaneously. Thus, the frozen particle compositions can be made whilepropelled, the frozen particle compositions can be made whileaccelerated, the frozen particle compositions can be made while ejected,or any combination thereof.

In one embodiment, the one or more frozen particle compositions aredelivered or administered by an inkjet printer-type apparatus or device,by a thermal bubble device, by ultrasound-mediated transdermal drugtransport, or by other device. When a voltage is applied, an inkjet-typeapparatus generates a pressure pulse by change in shape or size of achamber containing a fluid (or solid), and the pressure pulse drives thecontents from the chamber. In one particular instance, a high velocitydevice (such as a powderject, air guns, or slingshot type devices) isutilized for injection of particles formulated with at least onetherapeutic agent, for example, for therapy or prevention of a diseaseor condition.

For example, a powderject system, as described by Kumar and Philip(Trop. J. Pharm. Res., vol. 6, No. 1, pp. 633-644 (2007), which isincorporated herein by reference) propels frozen drug particles into theskin by means of high-speed gas flow (such as helium) that is usuallypainless and causes minimal bleeding or damage to the skin. (See alsoe.g., Tang et al., Pharm. Res., vol. 19, pp. 1160-69 (2002), which isincorporated herein by reference). As described by Kumar and Philip,particles contained in a cassette between two polycarbonate membraneslocated at the end of a chamber (Trop. J. Pharm. Res., vol. 6, No. 1,pp. 633-644 (2007), which is incorporated herein by reference). Asdescribed by Kumar and Philip, the polycarbonate membranes are rupturedwhen a carrier gas enters the chamber under high pressure, and the rapidexpansion of the gas forms a shock wave that travels down the nozzle ata speed of approximately 600-900 m/s. Kumar and Philip report drugparticle velocities of up to about 800 m/s at the nozzle exit, and themomentum density of the particles within the gas flow can be optimizedfor desired depth of penetration upon delivery to a biological tissue.(Trop. J. Pharm. Res., vol. 6, No. 1, pp. 633-644 (2007), which isincorporated herein by reference). In the powderject system, particlevelocity is controlled by nozzle geometry, membrane burst strength, andgas pressure. (See e.g., U.S. Pat. Nos. 5,630,796; and 5,699,880, whichare incorporated herein by reference).

Metered-dose transdermal sprays may also be used for delivery of atleast one composition as described herein. As described by Rathbone, etal., in one particular example, a topical solution containing a volatilethen nonvolatile vehicle including a therapeutic agent is administeredas a single-phase solution. (See Rathbone, et al., Modified Release ofDrug Delivery Technology, NY, Marcel Dekker, Inc. vol. 126, pp. 471-619(2004), which is incorporated herein by reference). A finitemetered-dose application of the formulation to intact skin results inevaporation of the volatile component, leaving the remaining nonvolatilepenetration enhancer or therapeutic agent to partition into the stratumcorneum and creating a reservoir of the therapeutic agent(s). (SeeRathbone, Ibid; and Kumar, et al., Trop. J. Pharm. Res., vol. 6, pp.633-644 (2007), each of which is incorporated herein by reference).

In addition to these particular examples of devices that can be utilizedfor administration of the compositions described herein, thecompositions can be administered in conjunction with other deliverydevices or avenues. Likewise, the compositions described herein forabrasion of at least one biological tissue can be delivered to the atleast one tissue by any means described herein. Some such means fordelivery of the compositions described herein include, but are notlimited to, ultrasound, iontophoresis (which involves applying anelectrical potential across skin or other tissue in order to increasepenetration of ionizable drugs), diffusion, electroporation,photomechanical waves (such as by producing pulses with Q-switched ormode-locked lasers to the skin or other tissue), needle-free injections,electro-osmosis, artificial vesicles, laser radiation, magnetophoresis(utilizing a diamagnetic substance for use with a magnetic field forincreased penetration of the composition into the biological tissue),microscissuining, controlled heat aided delivery (which involves heatingthe skin prior to or during therapeutic administration), or tattoos andetchings.

In one embodiment, Rathbone et al. have described artificial vesiclesthat mimic cell vesicles (such as TRANSFERSOMES®, from IDEA AG, Germany)can be utilized for administration of one or more composition describedherein. Artificial vesicles penetrate the skin barrier along thetranscutaneous moisture gradient and causes “virtual” pores between thecells in an organ without affecting its biological properties. (See,e.g., Modified Release Drug Delivery Technology, NY, Marcel Dekker,Inc., vol. 126, pp. 471-619 (2004), which is incorporated herein byreference). In addition, liposomes, and niosomes also serve as carriersand can be utilized in administration of at least one compositiondescribed herein.

In one embodiment, the one or more frozen particle compositions aregenerated by spraying a jet or mist of the composition constituents intoa low temperature environment (solid, liquid, gas, or any combinationthereof) such that the compositions freeze and form frozen particles. Inone embodiment, streams of frozen particles are extruded at lowtemperatures through fine ducts and into a low temperature environment.In one embodiment, the one or more frozen particles are propelledthrough a nozzle or other delivery apparatus. In one embodiment, the oneor more frozen particles are delivered by utilizing flash boiling of acold liquid. In one particular example, liquid nitrogen is flash boiledin order to accelerate, eject, or propel one or more frozen particlesfor delivery or administration to at least one cell, tissue, or subject.In one embodiment, the flash boiling is caused or enhanced by one ormore laser pulses (e.g., an infrared laser pulse). In one embodiment,the one or more frozen particles are prepared, delivered, oradministered by another means.

In certain instances, it is desirable to deliver the one or more frozenparticle compositions to at least one cell or tissue, or administer theone or more frozen particle compositions to at least one subject. In atleast one instance, the one or more frozen particle compositions includea plurality of frozen particle compositions that include two or moresubsets of frozen particle compositions that are delivered oradministered in sequential order. In one embodiment, the sequentialorder is predetermined, based on factors relating to, for example, theat least one cell or tissue, the at least one subject, or the at leastone frozen particle composition or therapeutic composition. In oneembodiment, the sequential order is determined during the course ofdelivery or administration of at least one of the one or more frozenparticles or at least one frozen particle composition or therapeuticcomposition. In one embodiment, the sequential order is determined by asoftware program. In one embodiment, the sequential order of delivery israndomized.

In one embodiment, the sequential order includes one or more subsets offrozen particle compositions that vary in size, shape, weight, density,location of delivery or administration, time of delivery oradministration, angle of delivery or administration, or velocity ofdelivery or administration. In one embodiment, one or more subsets offrozen particle compositions are delivered or administered according toa course of treatment (e.g., at least one subset of relatively smallfrozen particle compositions are administered first, followed by atleast one subset of relatively larger frozen particle compositions; atleast one subset of frozen particle compositions are administered in arelatively fast velocity, followed by at least one subset of frozenparticle compositions administered by a relatively slow velocity; atleast one subset of frozen particle compositions approximately shaped asspheroids are administered followed by at least one subset of frozenparticle compositions approximately shaped as bullets, etc.).

In one embodiment, the at least one frozen particle composition ispropelled using a pressure set at least about 1 psi, about 5 psi, about10 psi, about 20 psi, about 30 psi, about 40 psi, about 50 psi, at leastabout 100 psi, at least about 200 psi, at least about 300 psi, at leastabout 400 psi, at least about 450 psi, at least about 500 psi, at leastabout 600 psi, at least about 700 psi, at least about 800 psi, at leastabout 900 psi, at least about 1000 psi, at least about 1100 psi, atleast about 1200 psi, at least about 1300 psi, at least about 1400 psi,at least about 1500 psi, about 2000 psi, about 2500 psi, about 3000 psi,about 3500 psi, about 4000 psi, about 5000 psi, about 6000 psi, about7000 psi, about 8000 psi, about 9000 psi, about 10000 psi, about 20000psi, about 30000 psi, about 40000 psi, about 50000 psi, or any valuetherebetween.

In one embodiment, the at least one frozen particle composition ispropelled to or at a predetermined velocity, predetermined rate ofdelivery, or predetermined angle for delivery of the at least onecomposition to a desired location of the at least one biological tissue.In one embodiment, the velocity, rate, or angle of administration of theone or more frozen particle compositions are variable. In oneembodiment, a method of administering one or more frozen particlecompositions includes varying the rate, velocity, or angle at which thefrozen particle compositions are administered. In one embodiment, amethod includes multiple administrations of the one or more frozenparticle compositions, wherein at least two of the administrationsinclude different velocities, rates, or angles of delivery.

In one embodiment, the at least one frozen particle composition ispropelled to or at a velocity of approximately 1 m/s, approximately 5m/s, approximately 10 m/s, approximately 20 m/s, approximately 30 m/s,approximately 40 m/s, approximately 50 m/s, approximately 60 m/s,approximately 70 m/s, approximately 80 m/s, approximately 90 m/s,approximately 100 m/s, approximately 200 m/s, approximately 300 m/s,approximately 400 m/s, approximately 500 m/s, approximately 600 m/s,approximately 700 m/s, approximately 800 m/s, approximately 900 m/s,approximately 1000 m/s, approximately 1500 m/s, approximately 2000 m/s,approximately 3000 m/s, approximately 4000 m/s, approximately 5000 m/s,or any value greater or therebetween.

In one embodiment, the at least one frozen particle composition isaccelerated or ejected toward the at least one substrate (such as abiological tissue) to a velocity of approximately 1 m/s, approximately 5m/s, approximately 10 m/s, approximately 20 m/s, approximately 30 m/s,approximately 40 m/s, approximately 50 m/s, approximately 60 m/s,approximately 70 m/s, approximately 80 m/s, approximately 90 m/s,approximately 100 m/s, approximately 200 m/s, approximately 300 m/s,approximately 400 m/s, approximately 500 m/s, approximately 600 m/s,approximately 700 m/s, approximately 800 m/s, approximately 900 m/s,approximately 1000 m/s, approximately 1500 m/s, approximately 2000 m/s,approximately 3000 m/s, approximately 4000 m/s, approximately 5000 m/s,or any value greater or therebetween.

In one embodiment, delivering at least one frozen particle compositionto at least one substrate (such as a biological tissue) includesaccelerating, ejecting, or propelling a plurality of frozen particlecompositions toward the at least one substrate (including a biologicaltissue). Such a plurality of particles may include one embodimentwherein two or more frozen particle compositions of the pluralityinclude one or more similar agents. Likewise, a plurality of frozenparticle compositions may include one embodiment wherein two or morefrozen particle compositions include one or more dissimilar agents. Inone embodiment, the rate, velocity, or angle at which the one or morefrozen particle compositions are administered is variable.

As described herein, a plurality of frozen particle compositions orfrozen particles may include one or more subsets, which can be deliveredor administered in an order of operations. In one embodiment, the orderof operations includes delivery or administration in a pattern. In oneembodiment, the order of operations includes delivery or administrationin a predetermined pattern. In one embodiment, the order of operationsincludes delivery or administration in sequential order. In oneembodiment, the order of operations includes delivery or administrationat random.

For embodiments described herein, those having skill in the art willrecognize that the state of the art has progressed to the point wherethere is little distinction left between hardware, software, and/orfirmware implementations of aspects of systems; the use of hardware,software, and/or firmware is generally (but not always, in that incertain contexts the choice between hardware and software can becomesignificant) a design choice representing cost vs. efficiency tradeoffs.Those having skill in the art will appreciate that there are variousvehicles by which processes and/or systems and/or other technologiesdescribed herein can be effected (e.g., hardware, software, and/orfirmware), and that the preferred vehicle will vary with the context inwhich the processes and/or systems and/or other technologies aredeployed. For example, if an implementer determines that speed andaccuracy are paramount, the implementer may opt for a mainly hardwareand/or firmware vehicle; alternatively, if flexibility is paramount, theimplementer may opt for a mainly software implementation; or, yet againalternatively, the implementer may opt for some combination of hardware,software, and/or firmware. Hence, there are several possible vehicles bywhich the processes and/or devices and/or other technologies describedherein can be effected, none of which is inherently superior to theother in that any vehicle to be utilized is a choice dependent upon thecontext in which the vehicle will be deployed and the specific concerns(e.g., speed, flexibility, or predictability) of the implementer, any ofwhich may vary. Those skilled in the art will recognize that opticalaspects of implementations will typically employ optically-orientedhardware, software, and or firmware.

In some implementations described herein, logic and similarimplementations may include software or other control structures.Electronic circuitry, for example, may have one or more paths ofelectrical current constructed and arranged to implement variousfunctions as described herein. In some implementations, one or moremedia can be configured to bear a device-detectable implementation whensuch media hold or transmit device detectable instructions operable toperform as described herein. In some variants, for example,implementations may include an update or modification of existingsoftware or firmware, or of gate arrays or programmable hardware, suchas by performing a reception of or a transmission of one or moreinstructions in relation to one or more operations described herein.Alternatively or additionally, in some variants, an implementation mayinclude special-purpose hardware, software, firmware components, and/orgeneral-purpose components executing or otherwise invokingspecial-purpose components. Specifications or other implementations canbe transmitted by one or more instances of tangible transmission mediaas described herein, optionally by packet transmission or otherwise bypassing through distributed media at various times.

Alternatively or additionally, implementations may include executing aspecial-purpose instruction sequence or invoking circuitry for enabling,triggering, coordinating, requesting, or otherwise causing one or moreoccurrences of virtually any functional operations described herein. Insome variants, operational or other logical descriptions herein can beexpressed as source code and compiled or otherwise invoked as anexecutable instruction sequence. In some contexts, for example, C++ orother code sequences can be compiled or implemented in high-leveldescriptor languages (e.g., a logic-synthesizable language, a hardwaredescription language, a hardware design simulation, and/or other suchsimilar mode(s) of expression). For example, some or all of the logicalexpression can be manifested as a Verilog-type hardware description orother circuitry model before physical implementation in hardware. Thoseskilled in the art will recognize how to obtain, configure, and optimizesuitable transmission or computational elements, material supplies,actuators, or other structures in light of these teachings.

As indicated in FIGS. 7-9, one embodiment, a method 700 includescomparing 710 information regarding at least one aspect of administeringat least one frozen particle composition to at least one subject andinformation regarding at least one clinical outcome following receipt bythe at least one subject of at least one frozen particle composition;and providing output information optionally based on the comparison.

In one embodiment, the method includes determining at least onestatistical correlation 720. In one embodiment, the method includescounting the occurrence of at least one clinical outcome 730. In oneembodiment, the method includes determining at least one correlationbefore the administration of the at least one frozen particlecomposition 735. In one embodiment, information regarding at least oneaspect of administering at least one frozen particle compositionincludes information regarding the amount of at least one frozenparticle composition or therapeutic agent administered to at least onebiological tissue of a subject 740. In one embodiment, the informationregarding at least one aspect of administering or delivering at leastone frozen particle composition includes information regarding at leastone dimension of biological tissue penetration 750. In one embodiment,information regarding the at least one dimension of biological tissuepenetration includes information regarding at least one of depth, width,or breadth of administration of at least one frozen particle compositionto at least one biological tissue of at least one subject 760.

In one embodiment, the information regarding at least one aspect ofadministering at least one frozen particle composition includesinformation regarding two or more subjects with one or more commonattributes 770. In one embodiment, the one or more common attributesinclude genetic attributes, mental attributes, or psychologicalattributes 780. In at least on embodiment, the one or more commonattributes include genotype attributes or phenotype attributes 790.

In one embodiment, the one or more common attributes 797 include atleast one of height; weight; medical diagnosis; familial background;results on one or more medical tests; ethnic background; body massindex; age; presence or absence of at least one disease or condition;species; ethnicity; race; allergies; gender; thickness of epidermis;thickness of dermis; thickness of stratum corneum; keratin deposition;collagen deposition; blood vessel condition; skin condition; hair or furcondition; muscle condition; tissue condition; organ condition; nervecondition; brain condition; presence or absence of at least onebiological, chemical, or therapeutic agent in the subject; pregnancystatus; lactation status; genetic profile; proteomic profile; partial orwhole genetic sequence; partial or whole proteomic sequence; medicalhistory; lymph condition, or blood condition.

In one embodiment, the output information 810 includes at least one of aresponse signal, a comparison code, a comparison plot, a diagnosticcode, a treatment code, a test code, a code indicative of at least onetreatment received, a code indicative of at least one prescribedtreatment step, a code indicative of at least one vaccination delivered;a code indicative of at least one therapeutic agent delivered; a codeindicative of at least one diagnostic agent delivered; a code indicativeof at least one interaction of a delivered agent and at least onebiological or chemical agent in the subject; a code indicative of atleast one dispersion or location of at least one delivered agent; a codeindicative of at least one detection material delivered; a codeindicative of the depth of penetration of a delivered agent; or a codeindicative of the condition of at least one location of an administeredor delivered frozen particle composition. In one embodiment, the atleast one aspect of cellular or tissue abrasion or ablation includesinformation regarding at least one cellular or tissue source 820. In oneembodiment, the information regarding at least one tissue sourceincludes information regarding at least one abnormal cellular or tissuesource 830. In one embodiment, the information regarding at least onecellular or tissue source includes information regarding at least onetype of cell or tissue 840. In one embodiment, the cellular or tissuesource includes at least one cell or biological tissue described herein.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one of nitrogen, carbondioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, oxygen, air, argon, polyethylene glycol, acetone,ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, aceticacid, benzene, carbon tetrachloride, acetonitrile, hexane, methylenechloride, carboxylic acid, saline, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, or diethyl ether 850.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one major dimension ofapproximately one decimeter or less, or approximately one centimeter orless, approximately one millimeter or less, approximately one micrometeror less, approximately one nanometer or less, or any value therebetween860.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more reinforcement agents 870.In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more explosive materials 880. Inone embodiment, the receipt by the at least one subject of at least onefrozen particle composition or therapeutic composition is pursuant to atleast one clinical trial 900.

In one embodiment, the method includes creating at least one inclusioncriterion and at least one exclusion criterion for a clinical trialinvolving the at least one frozen particle composition or therapeuticcomposition 910. In one embodiment, the method further comprisessuggesting the inclusion of one or more of the at least one subject inat least one clinical trial 920. In one embodiment, the method furthercomprises suggesting the exclusion of one or more of the at least onesubject in at least one clinical trial 930. In certain instances,multiple subjects from multiple clinical trials are included. In oneembodiment, the method further includes using one or more of the atleast one comparison to predict at least one clinical outcome regardingat least one second subject 940. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 950. In one embodiment, the atleast one second subject is a plurality of people; and the methodfurther comprises segregating subject identifiers associated with theplurality of people in reference to the predicted at least one clinicaloutcome 960. In one embodiment, the at least one second subject is aplurality of people; and the method further comprises determining theeligibility of the at least one second subject for the at least oneclinical trial 970.

As indicated in FIGS. 10-12, at least one aspect includes a method 1000relating to predicting a clinical outcome of administering at least onefrozen particle therapeutic composition to at least one biologicaltissue of at least one first subject includes determining a similarityor a dissimilarity in information regarding at least one aspect ofadministering at least one therapeutic composition to the at least onebiological tissue of the at least one first subject to informationregarding at least one aspect of administering at least one therapeuticcomposition to the at least one biological tissue of the at least onesecond subject, wherein the at least one second subject attained aclinical outcome following receipt of the at least one frozen particletherapeutic composition; and providing output information optionallybased on the determination 1010.

In one embodiment, the information regarding the at least one aspect ofadministering at least one frozen particle therapeutic compositionincludes information 1020 regarding the amount of at least one frozenparticle therapeutic composition or therapeutic agent delivered to atleast one biological tissue of a subject. In one embodiment, theinformation regarding the at least one aspect of administering at leastone frozen particle therapeutic composition includes information 1030regarding at least one dimension of biological tissue penetration. Inone embodiment, the information regarding the at least one dimension ofbiological tissue penetration includes information 1040 regarding atleast one of depth, width, or breadth of delivery of at least one frozenparticle therapeutic composition to at least one biological tissue of atleast one subject; or information 1050 regarding two or more subjectswith common attributes.

In one embodiment, the one or more common attributes include geneticattributes, mental attributes, or psychological attributes 1060. In atleast on embodiment, the one or more common attributes include genotypeattributes or phenotype attributes 1070.

In one embodiment, the one or more common attributes 1080 include atleast one of height; weight; medical diagnosis; familial background;results on one or more medical tests; ethnic background; body massindex; age; presence or absence of at least one disease or condition;species; ethnicity; race; allergies; gender; thickness of epidermis;thickness of dermis; thickness of stratum corneum; keratin deposition;collagen deposition; blood vessel condition; skin condition; hair or furcondition; muscle condition; tissue condition; organ condition; nervecondition; brain condition; presence or absence of at least onebiological, chemical, or therapeutic agent in the subject; pregnancystatus; lactation status; genetic profile; proteomic profile; partial orwhole genetic sequence; medical history; partial or whole proteomicsequence; lymph condition, or blood condition.

In one embodiment, the output information 1100 includes at least one ofa response signal, a comparison code, a comparison plot, a diagnosticcode, a treatment code, a test code, a code indicative of at least onetreatment received, a code indicative of at least one prescribedtreatment step, a code indicative of at least one vaccination delivered;a code indicative of at least one therapeutic agent delivered; a codeindicative of at least one diagnostic agent delivered; a code indicativeof at least one interaction of a delivered agent and at least onebiological or chemical agent in the subject; a code indicative of atleast one dispersion or location of at least one delivered agent; a codeindicative of at least one detection material delivered; a codeindicative of the depth of penetration of a delivered agent; or a codeindicative of the condition of at least one location of an administeredor delivered frozen particle composition or therapeutic composition. Inone embodiment, the at least one aspect of cellular or tissue abrasionor ablation includes information regarding at least one cellular ortissue source 1110. In one embodiment, the information regarding atleast one tissue source includes information regarding at least oneabnormal cellular or tissue source 1120. In one embodiment, theinformation regarding at least one cellular or tissue source includesinformation regarding at least one type of cell or tissue 1130. In oneembodiment, the cellular or tissue source includes at least one cell orbiological tissue described herein.

In one embodiment, the at least one frozen particle composition includesat least one of nitrogen, carbon dioxide, hydrogen oxide, helium, neon,xenon, krypton, chlorine, bromine, methane, oxygen, air, argon,polyethylene glycol, acetone, ethyl acetate, dimethyl sulfoxide,dimethyl formamide, dioxane, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, acetic acid, benzene, carbontetrachloride, acetonitrile, hexane, methylene chloride, carboxylicacid, saline, Ringer's solution, lactated Ringer's solution, Hartmann'ssolution, acetated Ringer's solution, phosphate buffered solution,TRIS-buffered saline solution, Hank's balanced salt solution, Earle'sbalanced salt solution, standard saline citrate, HEPES-buffered saline,dextrose, glucose, or diethyl ether 1140.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one major dimension ofapproximately one decimeter or less, or approximately one centimeter orless, approximately one millimeter or less, approximately one micrometeror less, approximately one nanometer or less, or any value therebetween1150.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more reinforcement agents 1160.In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more explosive materials 1170.

In one embodiment, the receipt by the at least one subject of at leastone frozen particle composition or therapeutic composition is pursuantto at least one clinical trial 1200. In one embodiment, the methodfurther comprises determining at least one correlation before theadministration or delivery of the at least one frozen particlecomposition or therapeutic composition to at least one subject 1210. Theat least one subject includes, but is not limited to at least onesubject described herein.

In one embodiment, the method includes creating at least one inclusioncriterion and at least one exclusion criterion for a clinical trialinvolving the at least one frozen particle composition or therapeuticcomposition 1220. In one embodiment, the method further comprisessuggesting the inclusion of one or more of the at least one subject inat least one clinical trial 1230. In one embodiment, the method furthercomprises suggesting the exclusion of one or more of the at least onesubject in at least one clinical trial 1240. In certain instances,multiple subjects from multiple clinical trials are included. In oneembodiment, the method further includes using one or more of the atleast one comparison to predict at least one clinical outcome regardingat least one second subject 1250. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 1260. In one embodiment, themethod includes predicting at least one clinical outcome involving theat least one second subject, and the at least one second subject is aplurality of people; and the method further comprises segregatingsubject identifiers associated with the plurality of people in referenceto the predicted at least one clinical outcome 1270.

In one embodiment, the at least one second subject is a plurality ofpeople; and the method further comprises determining the eligibility ofthe at least one second subject for the at least one clinical trial1280.

As shown in FIGS. 13-15, one embodiment includes a system 1300 includingat least one computer program 1310, configured with a computer-readablemedium, for use with at least one computer system and wherein thecomputer program includes a plurality of instructions including but notlimited to one or more instructions 1320 for comparing informationregarding at least one aspect of at least one therapeutic administrationof at least one frozen particle composition or therapeutic compositionto at least one subject. In one embodiment, information 1330 regardingamount of the at least one frozen particle composition, therapeuticcomposition, or therapeutic agent administered to at least onebiological tissue of at least one subject. In one embodiment,information regarding at least one aspect of at least one therapeuticadministration of at least one frozen particle composition ortherapeutic composition includes information regarding at least onedimension of biological tissue penetration 1340. In one embodiment,information regarding at least one aspect of at least one therapeuticadministration of at least one frozen particle composition ortherapeutic composition includes information regarding at least one ofdepth, width, or breadth of administration of at least one frozenparticle composition or therapeutic composition to at least onebiological tissue of at least one subject 1350. In one embodiment,information regarding at least one aspect of at least one therapeuticadministration includes information regarding two or more subjects withone or more common attributes 1360. In one embodiment, the computingdevice is configured to communicate with at least one imaging device. Inone embodiment, the computing device is configured to communicate withat least one printing device. In one embodiment, the computing device isconfigured to communicate with at least one input device 1370.

In one embodiment, the information regarding at least one aspect oftherapeutic administration of at least one therapeutic compositionincludes information regarding at least one cellular or tissue source1400; information regarding at least one abnormal cellular or tissuesource 1410; or information regarding at least one type of cell ortissue 1420. In one embodiment, at least one frozen particle compositionor therapeutic composition includes at least one of nitrogen, carbondioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, oxygen, air or argon. In one embodiment, the at leastone frozen particle composition or therapeutic composition includes atleast one of polyethylene glycol, acetone, ethyl acetate, dimethylsulfoxide, dimethyl formamide, dioxane, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, acetic acid, benzene, carbontetrachloride, acetonitrile, hexane, methylene chloride, carboxylicacid, saline, Ringer's solution, lactated Ringer's solution, Hartmann'ssolution, acetated Ringer's solution, phosphate buffered solution,TRIS-buffered saline solution, Hank's balanced salt solution, Earle'sbalanced salt solution, standard saline citrate, HEPES-buffered saline,dextrose, glucose, or diethyl ether 1430. In one embodiment, at leastone frozen particle composition or therapeutic composition includes atleast one major dimension of approximately one decimeter or less,approximately one centimeter or less, approximately one millimeter orless, approximately one micrometer or less, approximately one nanometeror less, or any value therebetween 1440. In one embodiment, the at leastone frozen particle composition or therapeutic composition includes oneor more reinforcement agents 1450 or one or more explosive materials1460.

In one embodiment, the receipt by the at least one subject of at leastone frozen particle composition or therapeutic composition is pursuantto at least one clinical trial 1500. In one embodiment, the systemfurther comprises determining at least one correlation before thedelivery or administration of the at least one frozen particlecomposition or therapeutic composition to at least one subject 1510.

In one embodiment, the method includes creating at least one inclusioncriterion and at least one exclusion criterion for a clinical trialinvolving the at least one frozen particle composition or therapeuticcomposition 1520. In one embodiment, the instructions further comprisesuggesting the inclusion of one or more of the at least one subject inat least one clinical trial 1530. In certain instances, multiplesubjects from multiple clinical trials are included.

In one embodiment, the instructions include suggesting the exclusion ofone or more of the at least one subject in at least one clinical trial1540.

In one embodiment, a method includes using one or more of the at leastone comparison to predict at least one clinical outcome regarding atleast one second subject 1550. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 1560. In one embodiment, the atleast one second subject is a plurality of people; and furthercomprising segregating subject identifiers associated with the pluralityof people in reference to the predicted at least one clinical outcome1570.

In one embodiment, the using one or more of the at least one comparison,wherein the at least one second subject is a plurality of people; andfurther comprising determining the eligibility of the at least onesecond subject for the at least one clinical trial 1580.

As indicated in FIG. 16, one embodiment relates to a system 1600including at least one computer program 1610 configured with acomputer-readable medium, for use with at least one computer system andwherein the computer program includes a plurality of instructionsincluding but not limited to one or more instructions 1620 for comparinginformation regarding at least one aspect of at least one therapeuticadministration of at least one frozen particle therapeutic compositionto at last one subject, and information regarding at least one frozenparticle therapeutic composition involving at least one biologicaltissue of at least one subject; and one or more instructions forapplying one or more comparisons to the information regarding the atleast one aspect of therapeutic administration of at least one frozenparticle therapeutic composition to a plurality of people. In oneembodiment, the computer program includes one or more instructions 1630for segregating subject identifiers associated with the plurality ofpeople in reference to at least one of the one or more appliedcomparisons. In one embodiment, information regarding at least oneaspect of at least one therapeutic administration includes information1640 regarding the amount of at least one frozen particle composition,therapeutic composition or therapeutic agent administered to at leastone biological tissue of at least one subject; information 1650regarding at least one dimension of biological tissue penetration;information 1660 regarding at least one of depth, width, or breadth ofadministration of at least one frozen particle therapeutic compositionto at least one biological tissue of at least one subject. In oneembodiment, the computer program includes one or more instructions 1670for segregating individual identifiers associated with the plurality ofpeople in reference to at least one characteristic shared by two or moresubjects in the plurality of people.

As shown in FIG. 17, one embodiment relates to a computer programproduct 1700 that includes a signal bearing medium 1710 bearing at leastone of one or more instructions 1720 for receiving a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of one or more measurements relating toone or more physical attributes of a first subject; one or moreinstructions 1730 for comparing a value associated with the firstpossible dataset with a second dataset including values representativeof predictive regimen parameters from a second subject with one or moresimilar or dissimilar physical attributes; one or more instructions 1740for determining from the comparison at least one frozen particletherapeutic composition regimen for the first subject and outputinformation; one or more instructions 1750 for accessing the firstpossible dataset in response to the first input; one or moreinstructions 1760 for generating the first possible dataset in responseto the first input; one or more instructions 1770 for determining agraphical illustration of the first possible dataset; one or moreinstructions 1780 for determining a graphical illustration of the secondpossible dataset; and at least one generated output optionally based onthe determination.

In one embodiment, the computer program product includes a signalbearing medium that includes a computer-readable medium 1790. In oneembodiment, the signal bearing medium of the computer program productincludes a recordable medium 1792. In one embodiment, the computerprogram product includes a signal bearing medium that includes acommunications medium 1794.

As indicated in FIG. 18, one embodiment relates to a computer programproduct 1800 that includes a signal bearing medium 1810 bearing at leastone of one or more instructions 1820 for processing a first possibledataset, the first possible dataset including data representative of oneor more measurements relating to one or more physical attributes of afirst subject; one or more instructions 1830 for comparing a valueassociated with the first possible dataset with a second datasetincluding values representative of predictive regimen parameters from asecond subject with one or more similar or dissimilar physicalattributes; one or more instructions 1840 for determining from thecomparison at least one frozen particle composition or therapeuticcomposition treatment regimen for the first subject, and outputinformation.

As indicated in FIG. 19, one embodiment relates to a computer programproduct 1900 that includes a signal bearing medium 1910 bearing at leastone of one or more instructions 1920 responsive to a first possibledataset, the first possible dataset including data representative of oneor more measurements relating to one or more physical attributes of afirst subject; one or more instructions 1930 for comparing a valueassociated with the first possible dataset with a second datasetincluding values representative of predictive regimen parameters for asecond subject with one or more similar or dissimilar physicalattributes; one or more instructions 1940 for determining from thecomparison at least one frozen particle composition or therapeuticcomposition treatment regimen for the first subject; and outputinformation optionally based on the determination.

As shown in FIG. 20, one embodiment relates to a computer programproduct 2000 that includes a signal bearing medium 2010 bearing at leastone of one or more instructions 2020 for receiving a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of one or more measurements relating toone or more physical attributes of a subject; one or more instructions2030 for comparing a value associated with the first possible datasetwith a second dataset including values representative of parametersrelating to one or more expected biological changes followingadministration of one or more frozen particle compositions ortherapeutic compositions; one or more instructions 2040 for determiningfrom the comparison at least one biological change followingadministration of one or more frozen particle compositions ortherapeutic compositions to the subject; at least one generated outputoptionally based on the determination.

In one embodiment, the computer program product includes one or moreinstructions 2050 for accessing the first possible dataset in responseto the first input. In one embodiment, the computer program productincludes one or more instructions 2060 for generating the first possibledataset in response to the first input.

In one embodiment, the computer program product includes one or moreinstructions 2070 for determining a graphical illustration of the firstpossible dataset. In one embodiment, the computer program productincludes one or more instructions 2080 for determining a graphicalillustration of the second possible dataset. In one embodiment, thesignal bearing medium includes a computer-readable medium 2090. In oneembodiment, the signal bearing medium includes a recordable medium 2092.In one embodiment, the signal bearing medium includes a communicationsmedium 2094.

As indicated in FIG. 21, one embodiment a computer program product 2100includes a signal bearing medium 2110 bearing at least one of one ormore instructions 2120 for processing a first input associated with afirst possible dataset, the first possible dataset including datarepresentative of one or more measurements relating to one or morephysical attributes of a subject; one or more instructions 2130 forcomparing a value associated with the first possible dataset with asecond dataset including values representative of parameters relating toone or more expected biological changes following administration of oneor more frozen particle compositions or therapeutic compositions; one ormore instructions 2140 for determining from the comparison at least onebiological change following administration of one or more frozenparticle compositions or therapeutic compositions to the subject; atleast one generated output optionally based on the determination.

As shown in FIG. 22, one embodiment relates to a computer programproduct 2200 includes a signal bearing medium 2210 bearing at least oneof one or more instructions 2220 responsive to a first possible dataset,the first possible dataset including data representative of one or moremeasurements relating to one or more physical attributes of a subject;one or more instructions 2230 for comparing a value associated with thefirst possible dataset with a second dataset including valuesrepresentative of parameters relating to one or more expected biologicalchanges following administration of one or more frozen particlecompositions or therapeutic compositions; one or more instructions 2240for determining from the comparison at least one biological changefollowing administration of one or more frozen particle compositions ortherapeutic compositions to the subject; and output informationoptionally based on the determination.

As indicated in FIGS. 23-25, one embodiment, a method 2300 includescomparing 2310 information regarding at least one aspect of cellular ortissue abrasion or ablation of at least one biological tissue of atleast one subject and information regarding at least one clinicaloutcome following receipt by the at least one subject of at least onefrozen particle composition or therapeutic composition; and providingoutput information optionally based on the determination. In oneembodiment, the method includes determining at least one statisticalcorrelation 2320. In one embodiment, the method includes counting theoccurrence of at least one clinical outcome 2330. In one embodiment, theinformation regarding at least one aspect of cellular or tissue abrasionor ablation includes information regarding quantity of cells or tissueremoved or destroyed 2340. In one embodiment, the information regardingat least one aspect of cellular or tissue abrasion or ablation includesinformation regarding at least one dimension of cellular or tissueremoval or destruction, or removal or destruction of other materials,such as plaque, extracellular matrix, collagen, elastin, protein, orother materials 2350. In one embodiment, information regarding the atleast one dimension of cellular removal or destruction includesinformation regarding at least one of depth, width, or breadth ofcellular removal or destruction 2360.

In one embodiment, the information regarding at least one aspect ofcellular or tissue abrasion or ablation includes information regardingtwo or more subjects with one or more common attributes 2370. In oneembodiment, the one or more common attributes include geneticattributes, mental attributes, or psychological attributes 2380. In atleast on embodiment, the one or more common attributes include genotypeattributes or phenotype attributes 2390.

In one embodiment, the one or more common attributes 2397 include atleast one of height; weight; medical diagnosis; familial background;results on one or more medical tests; ethnic background; body massindex; age; presence or absence of at least one disease or condition;species; ethnicity; race; allergies; gender; thickness of epidermis;thickness of dermis; thickness of stratum corneum; keratin deposition;collagen deposition; blood vessel condition; skin condition; hair or furcondition; muscle condition; tissue condition; organ condition; nervecondition; brain condition; presence or absence of at least onebiological, chemical, or therapeutic agent in the subject; pregnancystatus; lactation status; genetic profile; proteomic profile; partial orwhole genetic sequence; medical history; partial or whole proteomicsequence; lymph condition, or blood condition.

In one embodiment, the output information 2410 includes at least one ofa response signal, a comparison code, a comparison plot, a diagnosticcode, a treatment code, a test code, a code indicative of at least onetreatment received, a code indicative of at least one prescribedtreatment step, a code indicative of at least one vaccination delivered;a code indicative of at least one therapeutic agent delivered; a codeindicative of at least one diagnostic agent delivered; a code indicativeof at least one interaction of a delivered agent and at least onebiological or chemical agent in the subject; a code indicative of atleast one dispersion or location of at least one delivered agent; a codeindicative of at least one detection material delivered; a codeindicative of the depth of penetration of a delivered agent; or a codeindicative of the condition of at least one location of a delivered oradministered frozen particle composition. In one embodiment, the atleast one aspect of cellular or tissue abrasion or ablation includesinformation regarding at least one cellular or tissue source 2420. Inone embodiment, the information regarding at least one tissue sourceincludes information regarding at least one abnormal cellular or tissuesource 2430. In one embodiment, the information regarding at least onecellular or tissue source includes information regarding at least onetype of cell or tissue 2440. In one embodiment, the cellular or tissuesource includes at least one cell or biological tissue described herein.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one of nitrogen, carbondioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, oxygen, air, argon, polyethylene glycol, acetone,ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, aceticacid, benzene, carbon tetrachloride, acetonitrile, hexane, methylenechloride, carboxylic acid, saline, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, or diethyl ether 2450.

In one embodiment, the at least one frozen particle composition includesat least one major dimension of approximately one decimeter or less, orapproximately one centimeter or less, approximately one millimeter orless, approximately one micrometer or less, approximately one nanometeror less, or any value therebetween 2460.

In one embodiment, the at least one frozen particle composition includesone or more reinforcement agents 2470. In one embodiment, the at leastone frozen particle composition includes one or more explosive materials2480. In one embodiment, the receipt by the at least one subject of atleast one frozen particle composition is pursuant to at least oneclinical trial 2500. In one embodiment, the method further comprisesdetermining at least one correlation 2510 before the delivery oradministration of the at least one frozen particle composition to atleast one subject. The at least one subject includes, but is not limitedto at least one subject described herein.

In one embodiment, the method includes creating at least one inclusioncriterion and at least one exclusion criterion for a clinical trialinvolving the at least one frozen particle composition or therapeuticcomposition 2515. In one embodiment, the method further comprisessuggesting the inclusion of one or more of the at least one subject inat least one clinical trial 2520. In one embodiment, the method furthercomprises suggesting the exclusion of one or more of the at least onesubject in at least one clinical trial 2530. In certain instances,multiple subjects from multiple clinical trials are included. In oneembodiment, the method further includes using one or more of the atleast one correlation to predict at least one clinical outcome regardingat least one second subject 2540. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 2550. In one embodiment, themethod further comprises predicting at least one clinical outcomeinvolving the at least one second subject, wherein the at least onesecond subject is a plurality of people; and segregating subjectidentifiers associated with the plurality of people in reference to thepredicted at least one clinical outcome 2560. In one embodiment, the atleast one second subject is a plurality of people; and the methodfurther comprises determining the eligibility of the at least one secondsubject for the at least one clinical trial 2570.

As indicated in FIGS. 26-28, one embodiment relates to a method 2600 ofpredicting a clinical outcome of at least one frozen particlecomposition treatment for at least one first subject includesdetermining 2610 a similarity or a dissimilarity in informationregarding at least one aspect of cellular or tissue abrasion or ablationof at least one biological tissue of at least one first subject toinformation regarding at least one aspect of cellular or tissue abrasionor ablation of at least one biological tissue of at least one secondsubject, wherein the at least one second subject attained a clinicaloutcome following receipt of the at least one frozen particlecomposition or therapeutic composition; and providing output informationoptionally based on the determination.

In one embodiment, the information regarding at least one aspect ofcellular or tissue abrasion or ablation includes information regardingthe quantity of cells or tissue removed or destroyed 2620. In oneembodiment, the information regarding at least one aspect of cellular ortissue abrasion or ablation includes information regarding at least onedimension of cellular, tissue, or other material removal or destruction2630. In one embodiment, the at least one dimension of cellular removalor destruction includes information regarding at least one of depth,width, or breadth of cellular removal or destruction 2640. In oneembodiment, the information regarding at least one aspect of cellular ortissue abrasion or ablation includes information regarding two or moresubjects with one or more common attributes 2650.

In one embodiment, the one or more common attributes include but are notlimited to genetic attributes, mental attributes, or psychologicalattributes 2660. In one embodiment, the one or more common attributesinclude genotype attributes or phenotype attributes 2670.

In one embodiment, the one or more common attributes include at leastone of height; weight; medical diagnosis; familial background; resultson one or more medical tests; ethnic background; body mass index; age;presence or absence of at least one disease or condition; species;ethnicity; race; allergies; gender; thickness of epidermis; thickness ofdermis; thickness of stratum corneum; keratin deposition; collagendeposition; blood vessel condition; skin condition; hair or furcondition; muscle condition; tissue condition; organ condition; nervecondition; brain condition; presence or absence of at least onebiological, chemical, or therapeutic agent in the subject; pregnancystatus; lactation status; medical history; genetic profile; proteomicprofile; partial or whole genetic sequence; partial or whole proteomicsequence; lymph condition, medical history, or blood condition 2680.

In one embodiment, the output information includes at least one of aresponse signal, a comparison code, a comparison plot, a diagnosticcode, a treatment code, a test code, a code indicative of at least onetreatment received, a code indicative of at least one prescribedtreatment step, a code indicative of at least one vaccination delivered;a code indicative of at least one therapeutic agent delivered; a codeindicative of at least one diagnostic agent delivered; a code indicativeof at least one interaction of a delivered agent and at least onebiological or chemical agent in the subject; a code indicative of atleast one dispersion or location of at least one delivered agent; a codeindicative of at least one detection material delivered; a codeindicative of the depth of penetration of a delivered agent; or a codeindicative of the condition of at least one location of a delivered oradministered frozen particle composition 2700.

In one embodiment, the information regarding at least one aspect ofcellular or tissue abrasion or ablation includes information regardingat least one cellular or tissue source 2710. In one embodiment, thecellular or tissue source includes but is not limited to at least onebiological tissue or cell described herein. In one embodiment, theinformation regarding at least one tissue source includes informationregarding at least one abnormal cellular or tissue source 2720. In oneembodiment, the information regarding at least one cellular or tissuesource includes information regarding at least one type of cell ortissue 2730. In one embodiment, the information regarding at least oneaspect of cellular or tissue abrasion or ablation includes informationregarding at least one type of cell or tissue.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one of nitrogen, carbondioxide, hydrogen oxide, helium, neon, xenon, krypton, chlorine,bromine, methane, oxygen, air or argon. In one embodiment, the at leastone frozen particle composition or therapeutic composition includes atleast one of polyethylene glycol, acetone, ethyl acetate, dimethylsulfoxide, dimethyl formamide, dioxane, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, acetic acid, benzene, carbontetrachloride, acetonitrile, hexane, methylene chloride, carboxylicacid, saline, Ringer's solution, lactated Ringer's solution, Hartmann'ssolution, acetated Ringer's solution, phosphate buffered solution,TRIS-buffered saline solution, Hank's balanced salt solution, Earle'sbalanced salt solution, standard saline citrate, HEPES-buffered saline,dextrose, glucose, or diethyl ether 2740.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one major dimension ofapproximately one decimeter or less, or approximately one centimeter orless, or approximately one millimeter or less, or approximately onemicrometer or less, or approximately one nanometer or less, or any valuetherebetween 2750.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more reinforcement agents 2760.In one embodiment, the at least one frozen particle composition ortherapeutic composition includes one or more explosive materials 2770.

In one embodiment, the receipt by the at least one subject of at leastone frozen particle composition or therapeutic composition is pursuantto at least one clinical trial 2800. In one embodiment, the methodincludes creating at least one inclusion criterion and at least oneexclusion criterion for a clinical trial involving the at least onefrozen particle composition or therapeutic composition 2810. In oneembodiment, the method further comprises suggesting the inclusion of oneor more of the at least one subject in at least one clinical trial 2820.In certain instances, multiple subjects from multiple clinical trialsare included. In one embodiment, the method includes suggesting theexclusion of one or more of the at least one subject in at least oneclinical trial 2830.

In one embodiment, a method includes using one or more of the at leastone determination to predict at least one clinical outcome regarding atleast one second subject 2840. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 2850. In one embodiment, the atleast one second subject is a plurality of people; and the methodfurther comprises segregating subject identifiers associated with theplurality of people in reference to the predicted at least one clinicaloutcome 2860.

In one embodiment, the using one or more of the at least one comparison,wherein the at least one second subject is a plurality of people; andthe method further comprises determining the eligibility of the at leastone second subject for the at least one clinical trial 2870.

As indicated in FIGS. 29-30, at least one aspect relates to a system2900 that includes at least one computing device 2910; one or moreinstructions 2920 that when executed on the at least one computingdevice cause the at least one computing device to receive a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of one or more measurements relating toone or more physical attributes of a first subject; one or moreinstructions 2930 that when executed on the at least one computingdevice cause the at least one computing device to compare a valueassociated with the first possible dataset with a second datasetincluding values representative of predictive regimen parameters relatedto a second subject with one or more similar or dissimilar physicalattributes; one or more instructions 2940 that when executed on the atleast one computing device cause the at least one computing device todetermine from the comparison at least one frozen particle compositiontreatment regimen for the first subject; and at least one generatedoutput optionally based on the determination; one or more instructions2950 that when executed on the at least one computing device cause theat least one computing device to access the first possible dataset inresponse to the first input; one or more instructions 2960 that whenexecuted on the at least one computing device cause the at least onecomputing device to generate the first possible dataset in response tothe first input; one or more instructions 2970 that when executed on theat least one computing device cause the at least one computing device todetermine a graphical illustration of the possible dataset; or one ormore instructions 3000 that when executed on the at least one computingdevice cause the at least one computing device to determine a graphicalillustration of the second possible dataset. In one embodiment, thetreatment regimen includes at least one of cellular or tissue removal,cellular or tissue ablation, debridement, delivery of at least onetherapeutic agent, cleaning one or more wounds, removing material fromat least one biological tissue, or removing material from at least oneblood vessel 3005. In at least one nitrogen, carbon dioxide, hydrogenoxide, helium, neon, xenon, krypton, chlorine, bromine, methane, oxygen,air, argon, polyethylene glycol, acetone, ethyl acetate, dimethylsulfoxide, dimethyl formamide, dioxane, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, acetic acid, benzene, carbontetrachloride, acetonitrile, hexane, methylene chloride, carboxylicacid, saline, Ringer's solution, lactated Ringer's solution, Hartmann'ssolution, acetated Ringer's solution, phosphate buffered solution,TRIS-buffered saline solution, Hank's balanced salt solution, Earle'sbalanced salt solution, standard saline citrate, HEPES-buffered saline,dextrose, glucose, or diethyl ether 3008.

In one embodiment, the at least one computing device includes one ormore desktop computer, workstation computer, computing system includinga cluster of processors, a networked computer, a tablet personalcomputer, a laptop computer, a mobile device, a mobile telephone, or apersonal digital assistant computer 3010. In one embodiment, the atleast one computing device is configured to communicate with a databaseto access the first possible dataset 3020. In one embodiment, the atleast one computing device is configured to communicate with a frozenparticle composition selecting apparatus, a frozen particle compositiongenerating apparatus, or both 3030.

As shown in FIGS. 31-32, at least one aspect relates to a system 3100including circuitry 3110 for receiving a first input associated with afirst possible dataset, the first possible dataset including datarepresentative of one or more measurements relating to one or morephysical attributes of a first subject; circuitry 3120 for comparing avalue associated with the first possible dataset with a second datasetincluding values representative of predictive regimen parameters relatedto a second subject with one or more similar or dissimilar physicalattributes; circuitry 3125 for determining from the comparison at leastone frozen particle composition treatment regimen for the first subject;circuitry 3128 for selecting at least one of quality or quantity relatedto one or more frozen particle compositions, method of administration ofone or more frozen particle compositions, administration location of oneor more frozen particle compositions, content of one or more frozenparticle compositions, timing of administration of one or more frozenparticle compositions, decrease in physical dimension of one or morefrozen particle compositions or time interval between at least twodeliveries with one or more frozen particle compositions.

In one embodiment, the system includes circuitry 3130 for determiningfrom the comparison at least one frozen particle composition treatmentregimen for the first subject; and circuitry 3140 for providing outputinformation optionally based on the comparison. In one embodiment, thecircuitry for receiving a first input associated with a first possibledataset includes circuitry 3200 for receiving one or more measurementsrelating to one or more physical attributes including at least one ofheight; weight; body mass index; age; presence or absence of at leastone disease or condition; species; ethnicity; race; allergies; gender;thickness of epidermis; thickness of dermis; thickness of stratumcorneum; keratin deposition; collagen deposition; blood vesselcondition; skin condition; hair or fur condition; muscle condition;tissue condition; organ condition; nerve condition; brain condition;presence or absence of at least one biological, chemical, or therapeuticagent in the subject; pregnancy status; lactation status; geneticprofile; medical history; proteomic profile; partial or whole geneticsequence; partial or whole proteomic sequence; medical history; lymphcondition, or blood condition.

In one embodiment, the system includes circuitry 3210 for selecting thecombination of at least two parameters selected from quality or quantityrelated to one or more frozen particle compositions, method ofadministration of one or more frozen particle compositions,administration location of one or more frozen particle compositions,content of one or more frozen particle compositions, timing ofadministration of one or more frozen particle compositions, decrease ina physical dimension of one or more frozen particle compositions, ortime interval between at least two administrations or deliveries withone or more frozen particle compositions.

In one embodiment, the system includes circuitry 3220 for selecting thecombination of at least two parameters selected from quality or quantityrelated to one or more frozen particle compositions, method ofadministration of one or more frozen particle compositions,administration location of one or more frozen particle compositions,content of one or more frozen particle compositions, timing ofadministration of one or more frozen particle compositions, decrease ina physical dimension of one or more frozen particle compositions, ortime interval between at least two administrations with one or morefrozen particle compositions.

In one embodiment, the system includes circuitry 3230 for selecting atleast one of a clinical outcome; secondary effects related to thetreatment; disease stage; longevity; or vaccination administration. Inone embodiment, the clinical outcome 3240 includes a positive clinicaloutcome or a negative clinical outcome. In one embodiment, the clinicaloutcome includes one or more adverse effect, failure to attain aclinical endpoint of a clinical trial, failing to attain a beneficialeffect, or measurement of at least one biochemical, biological orphysiological parameter 3250.

FIGS. 33-35 illustrate a partial view of a system 3300 including atleast one computer program 3310 configured with a computer-readablemedium, for use with at least one computer system and wherein thecomputer program includes a plurality of instructions including but notlimited to one or more instructions 3320 for determining at least onecomparison between information regarding at least one aspect of cellularor tissue abrasion or ablation of at least one biological tissue of atleast one subject and information regarding at least one clinicaloutcome following receipt by the at least one subject of at least onefrozen particle composition. In one embodiment, the system includes oneor more instructions 3330 for determining at least one statisticalcorrelation. In one embodiment, the system includes one or moreinstructions 3340 for counting the occurrence of at least one clinicaloutcome. In one embodiment, information regarding at least one aspect ofcellular or tissue abrasion or ablation includes information 3350regarding quantity of cells or tissue removed or destroyed; information3360 regarding at least one dimension of cellular, tissue or othermaterial removal or destruction; information 3370 regarding at least oneof depth, width, or breadth of cellular removal or destruction; orinformation 3380 regarding two or more subjects with one or more commonattributes. In one embodiment, the information regarding at least oneaspect of cellular or tissue abrasion or ablation includes information3400 regarding at least one cellular or tissue source, includinginformation 3410 regarding at least one abnormal cellular or tissuesource or information 3420 regarding at least one type of cell ortissue.

In one embodiment, the at least one frozen particle composition ortherapeutic composition includes at least one of polyethylene glycol,acetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, aceticacid, benzene, carbon tetrachloride, acetonitrile, hexane, methylenechloride, carboxylic acid, saline, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, or diethyl ether 3430. In oneembodiment, at least one frozen particle composition includes at leastone major dimension of approximately one decimeter or less,approximately one centimeter or less, approximately one millimeter orless, approximately one micrometer or less, approximately one nanometeror less, or any value therebetween 3440. In one embodiment, the at leastone frozen particle composition includes one or more reinforcementagents 3450. In one embodiment, the at least one frozen particlecomposition includes one or more explosive materials 3460.

In one embodiment, the receipt by the at least one subject of at leastone frozen particle composition or therapeutic composition is pursuantto at least one clinical trial 3500. In one embodiment, the systemfurther comprises one or more instructions for determining at least onecomparison before the delivery or administration of the at least onefrozen particle composition or therapeutic composition to at least onesubject 3510.

In one embodiment, the system includes one or more instructions forcreating at least one inclusion criterion and at least one exclusioncriterion for a clinical trial involving the at least one frozenparticle composition or therapeutic composition 3520. In one embodiment,the system further comprises one or more instructions for suggesting theinclusion of one or more of the at least one subject in at least oneclinical trial 3530. In certain instances, multiple subjects frommultiple clinical trials are included.

In one embodiment, the system further includes one or more instructionsfor suggesting the exclusion of one or more of the at least one subjectin at least one clinical trial 3540. In one embodiment, the systemincludes one or more instructions for using one or more of the at leastone comparison to predict at least one clinical outcome regarding atleast one second subject 3550. In one embodiment, the at least onesecond subject has not received the at least one frozen particlecomposition or therapeutic composition 3560. In one embodiment, thesystem includes predicting at least one clinical outcome involving theat least one second subject, wherein the at least one second subject isa plurality of people; and segregating subject identifiers associatedwith the plurality of people in reference to the predicted at least oneclinical outcome 3570. In one embodiment, the at least one secondsubject is a plurality of people; and the system further comprisesdetermining the eligibility of the at least one second subject for theat least one clinical trial 3580.

As indicated in FIG. 36, at least one aspect relates to a system 3600that includes at least one computer program 3610, configured with acomputer-readable medium, for use with at least one computer system andwherein the computer program includes a plurality of instructionsincluding but not limited to one or more instructions 3620 for comparinginformation regarding at least one aspect of cellular or tissue abrasionor ablation of at least one biological tissue of at least one subjectand information regarding at least one frozen particle compositioninvolving the at least one biological tissue of at least one subject;and one or more instructions 3630 for applying one or more comparisonsto information regarding at least one aspect of cellular or tissueabrasion or ablation regarding a plurality of people. In one embodiment,one or more instructions 3640 for segregating subject identifiersassociated with the plurality of people in reference to at least one ofthe one or more applied comparisons. In one embodiment, the informationregarding at least one aspect of cellular or tissue abrasion or ablationincludes information 3650 regarding quantity of cells or tissue removedor destroyed; information 3660 regarding at least one dimension ofcellular, tissue or other material removal or destruction; orinformation 3670 regarding at least one of depth, width, or breadth ofcellular removal or destruction. In one embodiment, the system includesone or more instructions 3680 for segregating individual identifiersassociated with the plurality of people in reference to at least onecharacteristic shared by two or more subjects of the plurality ofpeople.

As indicated in FIG. 37, at least one aspect relates to a method 3700comprising accepting a first input 3710 associated with at least onecharacteristic of at least one biological tissue to be at leastpartially constructed or at least partially reconstructed; accepting asecond input 3720 associated with at least one parameter of at leastpartially constructing or at least partially reconstructing the at leastone biological tissue by administering one or more frozen particlecompositions including at least one agent. In one embodiment, the atleast one agent 3730 includes one or more of a therapeutic agent,adhesive agent, abrasive, reinforcement agent, explosive material, orbiological remodeling agent. In one embodiment, administering 3740 theone or more frozen particle compositions includes administering the oneor more frozen particle compositions to at least one substrate. In oneembodiment, the at least one substrate 3750 includes one or more of acell, tissue, organ, structure, or device.

In one embodiment, the method includes processing results 3760 of thefirst input and the second input. In one embodiment, processing resultsof the first input and the second input includes electronicallyprocessing 3770 results of the first input and the second input. In oneembodiment, processing results of the first input and the second inputincludes 3780 electronically processing results of the first input andthe second input by utilizing one or more of Gaussian smoothing,scaling, homomorphic filtering, parametric estimation techniques,Boolean operations, Monte Carlo simulations, wavelet based techniques,mirroring, smoothing, gradient weighted partial differential equationsmoothing, NURBS, polygonal modeling, splines and patches modeling, ormodification of a CAD design.

As indicated in FIG. 38, in one embodiment, the first input 3810includes one or more values related to the at least one characteristicof at least one biological tissue. In one embodiment, the first inputincludes one or more spatial addresses 3820 associated with the at leastone characteristic of at least one biological tissue. In one embodiment,the first input includes one or more of x, y, or z coordinates 3830associated with the at least one characteristic of at least onebiological tissue.

In one embodiment, the at least one characteristic 3840 of at least onebiological tissue to be at least partially constructed or at leastpartially reconstructed includes one or more of: morphological feature,anatomical feature, histological feature, tissue hierarchical level,scaffold feature, vascular structure feature, heterogenous tissuefeature, mechanical feature, volumetric feature, geometric feature,volumetric representation, mechanical feature, deformation, kinematicfeature, surface contour feature, cytometric feature, cell aggregation,cell growth, cell-cell interaction, cell-tissue interaction, biomimeticdesign, cell pattern, cell deposition, organ hierarchical level, tissuemicrostructure, cellular microstructure, cell junction feature, tissuejunction feature, cell-tissue classification, hard tissueclassification, soft tissue classification, tumor diagnosis, or otherfeature.

In one embodiment, the at least one characteristic 3850 of at least onebiological tissue includes one or more of cellular type, cellularfunction, cellular size, cellular constitution, cellular architecture,cellular durability, cellular source, tissue type, tissue constitution,tissue size, tissue shape, tissue function, tissue architecture, tissuesource, tissue durability, organ type, organ constitution, organ size,organ shape, organ function, organ architecture, organ source, or organdurability. In one embodiment, the first input 3860 includes one or moretemporal addresses associated with the at least one characteristic of atleast one biological tissue.

As indicated in FIG. 39, in one embodiment, the first input 3910includes one or more values derived from at least one image of the atleast one biological tissue. In one embodiment, the at least one image3920 includes one or more images acquired by one or more of opticalcoherence tomography, computer-assisted tomography scan, computedtomography, magnetic resonance imaging, positron-emission tomographyscan, ultrasound, x-ray, electrical-impedance monitoring, microscopy,spectrometry, flow cytommetry, radioisotope imaging, thermal imaging,multiphoton calcium-imaging, photography, or in silico generation.

In one embodiment, the at least one biological tissue 3930 is located inat least one of in situ, in vitro, in vivo, in utero, in planta, insilico, or ex vivo. In one embodiment, the at least one biologicaltissue 3940 is at least partially located in at least one subject. Inone embodiment, the method further comprises accepting a third input3950 associated with at least one feature of the at least one subject.In one embodiment, the at least one feature 3960 of the at least onesubject includes one or more of age, gender, genotype, phenotype,proteomic profile, or health condition.

As indicated in FIGS. 40-41, In one embodiment, the processing results4010 of the first input and the second input includes determining atleast one parameter of at least partially constructing or at leastpartially reconstructing the at least one biological tissue with one ormore frozen particle compositions from one or more values derived fromat least one image of the at least one biological tissue. In oneembodiment, the second input 4020 includes one or more values related tothe at least one parameter of at least partially constructing or atleast partially reconstructing the at least one biological tissue byadministering one or more frozen particle compositions to the at leastone substrate. In one embodiment, 4130 the one or more values related tothe at least one parameter of constructing or reconstructing the atleast one biological tissue includes one or more predictive values.

In one embodiment, the at least one parameter 4030 of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue includes one or more of porosity of the at least onesubstrate, pore size of the at least one substrate, interconnectivity ofthe pores of the at least one substrate, transport properties of the atleast one substrate, cell-tissue formation of the at least onesubstrate, mechanical strength of the at least one substrate, abilityfor attachment or distribution of the at least one agent included in theone or more frozen particle compositions to the at least one substrate,ability for attachment or distribution of one or more cells or tissuesto the at least one substrate, facilitation of at least one nutrient, ortissue formation or tissue growth associated with the at least onesubstrate.

In one embodiment, the at least one parameter 4040 of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions includes one or more of: design of plot or model foradministration of one or more frozen particle compositions, constitutionof the one or more frozen particle compositions, formulation of the oneor more frozen particle compositions, size of the one or more frozenparticle compositions, shape of the one or more frozen particlecompositions, angle of administration of the one or more frozen particlecompositions, velocity of administration of the one or more frozenparticle compositions, quantity of frozen particle compositionsadministered, rate of administration of more than one frozen particlecomposition, spatial location for administration of one or more frozenparticle compositions, temporal location for administration of one ormore frozen particle compositions, method of administration of one ormore frozen particle compositions, timing of administration of one ormore frozen particle compositions, modulation of administration of oneor more frozen particle compositions, deposition of one or more frozenparticle compositions, or rate of deposition of at least one agent.

In one embodiment, the at least one parameter 4110 of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions includes at least one parameter relating to at leastpartially ablating or at least partially abrading one or more surfacesof the at least one biological tissue with the one or more frozenparticle compositions.

In one embodiment, the at least one parameter 4120 of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions includes at least one parameter relating to administeringat least one of a therapeutic agent, adhesive agent, biologicalremodeling agent, reinforcement agent, abrasive, or explosive materialwith the one or more frozen particle compositions.

In one embodiment, the spatial location 4140 for administration of oneor more frozen particle compositions includes one or more of x, y, or zcoordinates. In one embodiment, the processing results 4150 includescomparing at least one value related to the first input associated withthe at least one characteristic of at least one biological tissue to beat least partially constructed or at least partially reconstructed withat least one value related to at least one image of a target biologicaltissue. In one embodiment 4160, the image of a target biological tissueincludes an image of a similar biological tissue, or an image of adissimilar biological tissue.

As indicated in FIG. 42, the processing results 4210 includes comparingat least one value related to the second input associated with the atleast one parameter of at least partially constructing or at leastpartially reconstructing the at least one biological tissue with atleast one value related to another administration of one or more frozenparticle compositions. In one embodiment 4220, the processing resultsincludes determining one or more differences in at least one valuerelated to the first input and at least one value related to at leastone image of the at least one biological tissue or a similar biologicaltissue. In one embodiment 4230, the processing results includesdetermining one or more differences in at least one value related to thesecond input associated with the at least one parameter of at leastpartially constructing or at least partially reconstructing the at leastone biological tissue and at least one value related to anotheradministration of one or more frozen particle compositions to the atleast one substrate.

In one embodiment 4240, the processing results includes generating oneor more protocols for administering the one or more frozen particlecompositions. In one embodiment 4250, the processing results includesgenerating one or more blueprints for administering the one or morefrozen particle compositions. In one embodiment 4260, the one or moreblueprints include at least one of a two-dimesional plot or athree-dimensional model. In one embodiment 4270, the one or moreblueprints include at least one representation of at least one of organanatomy, morphology, tissue heterogeneity, scale of vascular system,geometry, internal architecture of an organ or tissue, internal orexternal boundary distinction of a tissue or organ, topology, ortomography.

As indicated in FIG. 43, the processing results 4310 includes: comparingone or more values related to the one or more characteristics of the atleast one biological tissue that are determined at two or more differenttimes to obtain one or more characteristic comparisons; comparing one ormore values related to the at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue at two or more different times to obtain one or moreparameter comparisons; comparing the one or more characteristiccomparisons with the one or more parameter comparisons to obtain one ormore characteristic-characteristic/parameter-parameter comparisons; andcomparing the one or morecharacteristic-characteristic/parameter-parameter comparisons to one ormore substantially similar results obtained for one or more other atleast partially constructed or at least partially reconstructedbiological tissues. In one embodiment 4320, the administering one ormore frozen particle compositions includes depositing the at least oneagent on the at least one substrate.

As indicated in FIG. 44, the method further comprises 4410 displayingresults of the processing. In one embodiment 4420, the displayingresults of the processing includes displaying the results on one or moreactive displays. In one embodiment 4430, the displaying results of theprocessing includes displaying the results on one or more passivedisplays. In one embodiment 4440, the displaying results of theprocessing includes displaying the results of the processing in at leastone of numeric format, graphical format, or audio format.

In one embodiment 4450, the displaying results of the processingincludes displaying a comparison of at least one biological tissue thathas been at least partially constructed or at least partiallyreconstructed. In one embodiment 4460, the displaying results of theprocessing includes displaying a comparison of at least one subject withone or more other subjects. In one embodiment 4470, the displayingresults of the processing includes displaying one or more differences inthe comparison of at least one value related to the first input and atleast one value related to at least one image of a biological tissue. Inone embodiment 4480, the displaying results of the processing includesdisplaying one or more differences in the comparison of at least onevalue related to the second input and at least one value related toanother administration of one or more frozen particle compositions.

As indicated in FIG. 45, the method further comprises transmitting 4510one or more signals that include information related to the processingresults of the first input and the second input. In one embodiment 4520,the transmitting one or more signals includes transmitting one or moresignals associated with selection of one or more frozen particlecompositions for administration. In one embodiment 4530, thetransmitting one or more signals includes transmitting one or moresignals associated with selection of one or more of a biologicalremodeling agent, adhesive agent, abrasive, therapeutic agent,reinforcement agent, or explosive material associated with the one ormore frozen particle compositions. In one embodiment 4540, thetransmitting one or more signals includes transmitting one or moresignals associated with comparing the information related to theprocessing results of the first input and the second input.

As indicated in FIG. 46, the one or more frozen particle compositions4610 include one or more frozen particles including at least one ofhydrogen oxide, nitrogen, oxygen, air, helium, neon, argon, xenon,chlorine, bromine, carbon dioxide, acetone, ethyl acetate, dimethylsulfoxide, dimethyl formamide, dioxane, tetrahydrofuran, acetronitrile,acetic acid, n-butanol, isopropanol, n-propanol,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, benzene,carbon tetrachloride, acetonitrile, hexane, dichloromethane, methylenechloride, carboxylic acid, saline, standard saline citrate, methane,toluene, chloroform, polyethylene glycol, acetic acid, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,standard saline citrate, HEPES-buffered saline, dextrose, glucose,methane, or diethyl ether.

In one embodiment 4620, the at least one agent includes one or more ofan adhesive agent, therapeutic agent, reinforcement agent, abrasive,explosive material, or biological remodeling agent. In one embodiment4630, at least one of the adhesive agent, therapeutic agent,reinforcement agent, abrasive, explosive material, or biologicalremodeling agent is substantially in the form of at least one of anorganic or inorganic small molecule, clathrate or caged compound,protocell, coacervate, microsphere, Janus particle, proteinoid,laminate, helical rod, liposome, macroscopic tube, niosome, sphingosome,toroid, vesicular tube, vesicle, small unilamellar vesicle, largeunilamellar vesicle, large multilamellar vesicle, multivesicularvesicle, lipid layer, lipid bilayer, micelle, organelle, cell, membrane,nucleic acid, peptide, polypeptide, protein, oligosaccharide,polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, bone cement,copolymer, cell receptor, adhesion molecule, cytokine, chemokine,immunoglobulin, antibody, antigen, platelet, extracellular matrix,blood, plasma, cell ligand, zwitterionic material, cationic material,oligonucleotide, nanotube, or piloxymer.

As indicated in FIG. 47, the one or more explosive materials 4710include at least one of a carbonate, carbon dioxide, nitroglycerine,acid, base, epoxy, acrylic polymer or copolymer, acrylamide polymer orcopolymer, urethane, hypoxyapatite, or reactive metal. In one embodiment4720, the at least one adhesive agent includes one or more of an acrylicpolymer or copolymer, acrylamide polymer or copolymer polymer orcopolymer, acrylamide polymer or copolymer, polyacrylic acid, epoxy,urethane, gum arabic, polyester, polyhydroxyalkanoate, poly(L-lacticacid), polyglycolide, polylactic acid, polyether, polyol,polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, hydroxyapatite,polyelectrolyte, maleic polyelectrolyte, cellulose, resilin,cyanoacrylate, isocyanate, 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate, butyl-2-cyanoacrylate,methyl 2-cyanoacrylate, polyisohexylcyanoacrylate, fibrin, thrombin,fibrinogen, hyaluronate, chitin, Factor XIII, Factor XII, silk, nylon,collagen, glycosaminoglycan, selectin, polyurethane, methacrylate, orpolysulfide, polyanhydride, polydioxanone, poly-p-dioxanone, silicone,albumin, glutaraldehyde, polyethylene glycol, or gelatin.

In at least one embodiment 4730, the one or more reinforcement agentsinclude one or more of polyaramid, vinylester matrix, metal, ceramic,fiberglass, cellulose, broad carbide, aromatic polyamide, nylon, silk,rayon, acetate, modacrylic, olefin, acrylic, polyester, aromaticpolyester, poly-lactic acid, vinyon, saran, spandex, vinalon, aromaticnylon, vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell,orlon, zylon, high-performance polyethylene, polypyridobenzimidazole,vectran, acrylonitrile rubber, glass, copper, iron, steel, sodium,potassium, calcium, zinc, manganese, carbon, magnesium, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter.

As indicated in FIG. 48, the therapeutic agent 4810 includes at leastone of an anti-tumor agent, antimicrobial agent, anti-viral agent,analgesic, antiseptic, anesthetic, diagnostic agent, anti-inflammatoryagent, vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotic promoting factor, enzymatic agent,angiogenic factor, anti-angiogenic factor, hormone, vitamin, mineral,nutraceutical, cytokine, chemokine, probiotic, coagulant,anti-coagulant, phage, prodrug, prebiotic, blood sugar stabilizer,smooth muscle cell activator, epinephrine, adrenaline, neurotoxin,neuro-muscular toxin, Botulinum toxin type A, microbial cell orcomponent thereof, or virus or component thereof.

In one embodiment 4820 the at least one biological remodeling agentincludes one or more of a blood cell, chondrocyte, endothelial cell,hepatocyte, keratinocyte, myocyte, osteoblast, osteoclast, osteocyte,mesenchymal cell, stem cell, progenitor cell, or fibroblast. In oneembodiment, 4830, the at least one biological remodeling agent includesone or more of calcium phosphate, albumin, cytokine, pegylated cytokine,bone, cartilage, globulin, fibrin, thrombin, glutaraldehyde-crosslinkedpericardium, hide powder, hyaluronic acid, hydroxylapatite, keratin,ligament, nitinol, nucleic acid polymers, polyethylene, polylethyleneglycol, polyethylene glycol diacrylate, polyethylene terephthalatefiber, polyglycol, polylactate, polytetrafluoroethylene, polylacticacid, polyglycolic acid, polycaprolactone, PURAMATRIX™ self-assemblypeptide hydrogel fibers, linear aliphatic polyester, tendon, fibrinogen,hyaluronate, chitin, chitosan, methylcellulose, alginate, hyaluronicacid, agarose, cellulose, polyaldehyde gluronate, Factor XIII, FactorXII, silk, nylon, collagen, silicone, polyurethane, ceramic powder,elastin, pectin, wax, glycosaminoglycan, poly(α-hydroxyacid), selectin,glutaraldehyde, hydrophobic non-glycosylated protein, hydrogel, peptidehydrogel, or gelatin. In one embodiment 4840, the at least onebiological remodeling agent includes one or more of Type I collagen,Type II collagen, Type III collagen, Type VII collagen, Type X collagen,elastin fibers, or soluble elastin. In one embodiment 4850, the at leastone biological remodeling agent is included as part of a carrier thatassists in synthesis or activation of the at least one biologicalremodeling agent.

As indicated in FIGS. 49-51, a method 4900 comprises accepting input4910 associated with at least one parameter of at least partiallyconstructing or at least partially reconstructing at least onebiological tissue by administering one or more frozen particlecompositions; administering 4920 one or more frozen particlecompositions including at least one agent; wherein 4930 the at least oneagent includes one or more of a biological remodeling agent, therapeuticagent, reinforcement agent, explosive material, abrasive, or adhesiveagent; evaluating 4940 the at least one biological tissue for one ormore indicators related to deposition of at least one agent, tissueformation, or tissue growth; and transmitting 5110 one or more signalsthat include information related to the accepting input and informationrelated to the evaluating the at least one biological tissue.

In one embodiment 4950, the evaluating at least one biological tissuefor one or more indicators includes evaluating at least one of an assay,image, or gross assessment of the at least one biological tissue priorto, during, or subsequent to at least one administration of the one ormore frozen particle compositions. In one embodiment 4960, the assayincludes at least one technique that includes spectroscopy, microscopy,electrochemical detection, polynucleotide detection, histologicalexamination, biopsy analysis, fluorescence resonance energy transfer,electron transfer, enzyme assay, electrical conductivity, isoelectricfocusing, chromatography, immunoprecipitation, immunoseparation, aptamerbinding, filtration, electrophoresis, immunoassay, or radioactive assay.

In one embodiment 5020, the image includes at least one image acquiredby one or more of optical coherence tomography, computer-assistedtomography scan, computed tomography, magnetic resonance imaging,positron-emission tomography scan, ultrasound, x-ray,electrical-impedance monitoring, microscopy, spectrometry, flowcytommetry, radioisotope imaging, thermal imaging, multiphotoncalcium-imaging, photography, or in silico generation. In one embodiment5030, wherein the one or more indicators of tissue formation or growthinclude at least one of cell migration, cell attachment, cell retention,cell differentiation, cell proliferation, apoptosis, diffusion ofmaterials, angiogenesis, nucleic acid expression, protein translation,protein modification, carbohydrate production, carbohydrate secretion,fat production, fat secretion, or protein secretion.

In one embodiment 5040, the input associated with at least one parameterof at least partially constructing or at least partially reconstructingthe at least one biological tissue by administering one or more frozenparticle compositions includes one or more of: constitution of the oneor more frozen particle compositions, formulation of the one or morefrozen particle compositions, size of the one or more frozen particlecompositions, shape of the one or more frozen particle compositions,angle of administration of the one or more frozen particle compositions,velocity of administration of the one or more frozen particlecompositions, quantity of frozen particle compositions administered,rate of administration of more than one frozen particle composition,spatial location for administration of one or more frozen particlecompositions, temporal location for administration of one or more frozenparticle compositions, method of administration of one or more frozenparticle compositions, timing of administration of one or more frozenparticle compositions, modulation of administration of one or morefrozen particle compositions, deposition of one or more frozen particlecompositions, or rate of deposition of at least one agent.

In one embodiment 5120, the transmitting one or more signals includestransmitting one or more signals associated with selection of one ormore frozen particle compositions for administration. In one embodiment5130, the transmitting one or more signals includes transmitting one ormore signals associated with selection of one or more of a biologicalremodeling agent, adhesive agent, abrasive, therapeutic agent,reinforcement agent, or explosive material associated with the one ormore frozen particle compositions. In one embodiment 5140, theadministering one or more frozen particle compositions includesadministering the one or more frozen particle compositions to at leastone substrate. In one embodiment 5150, the at least one substrateincludes one or more of a cell, tissue, organ, structure, or device. Inone embodiment 5160, the one or more frozen particle compositionsinclude one or more frozen particles including at least one of hydrogenoxide, nitrogen, oxygen, air, helium, neon, argon, xenon, chlorine,bromine, carbon dioxide, acetone, ethyl acetate, dimethyl sulfoxide,dimethyl formamide, dioxane, tetrahydrofuran, acetronitrile, aceticacid, n-butanol, isopropanol, n-propanol, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, benzene, carbon tetrachloride,acetonitrile, hexane, dichloromethane, methylene chloride, carboxylicacid, saline, standard saline citrate, methane, toluene, chloroform,polyethylene glycol, acetic acid, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, methane, or diethyl ether.

As indicated in FIG. 52, the at least one agent 5210 includes one ormore of an adhesive agent, therapeutic agent, reinforcement agent,abrasive, explosive material, or biological remodeling agent. In oneembodiment 5220, the adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent issubstantially in the form of at least one of an organic or inorganicsmall molecule, clathrate or caged compound, protocell, coacervate,microsphere, Janus particle, proteinoid, laminate, helical rod,liposome, macroscopic tube, niosome, sphingosome, toroid, vesiculartube, vesicle, small unilamellar vesicle, large unilamellar vesicle,large multilamellar vesicle, multivesicular vesicle, lipid layer, lipidbilayer, micelle, organelle, cell, membrane, nucleic acid, peptide,polypeptide, protein, oligosaccharide, polysaccharide, glycopeptide,glycolipid, sphingolipid, glycosphingolipid, glycoprotein,peptidoglycan, lipid, carbohydrate, metalloprotein, proteoglycan,chromosome, cell nucleus, acid, base, buffer, protic solvent, aproticsolvent, nitric oxide, nitric oxide synthase, nitrous oxide, amino acid,micelle, polymer, bone cement, copolymer, cell receptor, adhesionmolecule, cytokine, chemokine, immunoglobulin, antibody, antigen,platelet, extracellular matrix, blood, plasma, cell ligand, zwitterionicmaterial, cationic material, oligonucleotide, nanotube, or piloxymer.

In one embodiment 5230, the one or more explosive materials include atleast one of a carbonate, carbon dioxide, nitroglycerine, acid, base,epoxy, acrylic polymer or copolymer, acrylamide polymer or copolymer,urethane, hypoxyapatite, or reactive metal. In one embodiment 5240, theat least one adhesive agent includes one or more of an acrylic polymeror copolymer, acrylamide polymer or copolymer polymer or copolymer,acrylamide polymer or copolymer, polyacrylic acid, epoxy, urethane, gumarabic, polyester, polyhydroxyalkanoate, poly(L-lactic acid),polyglycolide, polylactic acid, polyether, polyol, polyvinylpyrrolidone,pyroxylin, polymethylacrylate-isobutene-monoisopropylmaleate, siloxanepolymer, polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, hydroxyapatite,polyelectrolyte, maleic polyelectrolyte, cellulose, resilin,cyanoacrylate, isocyanate, 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate, butyl-2-cyanoacrylate,methyl 2-cyanoacrylate, polyisohexylcyanoacrylate, fibrin, thrombin,fibrinogen, hyaluronate, chitin, Factor XIII, Factor XII, silk, nylon,collagen, glycosaminoglycan, selectin, polyurethane, methacrylate, orpolysulfide, polyanhydride, polydioxanone, poly-p-dioxanone, silicone,albumin, glutaraldehyde, polyethylene glycol, or gelatin.

As indicated in FIG. 53, the one or more reinforcement agents 5310include one or more of polyaramid, vinylester matrix, metal, ceramic,fiberglass, cellulose, broad carbide, aromatic polyamide, nylon, silk,rayon, acetate, modacrylic, olefin, acrylic, polyester, aromaticpolyester, poly-lactic acid, vinyon, saran, spandex, vinalon, aromaticnylon, vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell,orlon, zylon, high-performance polyethylene, polypyridobenzimidazole,vectran, acrylonitrile rubber, glass, copper, iron, steel, sodium,potassium, calcium, zinc, manganese, carbon, magnesium, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter.

In one embodiment 5320, the therapeutic agent includes at least one ofan anti-tumor agent, antimicrobial agent, anti-viral agent, analgesic,antiseptic, anesthetic, diagnostic agent, anti-inflammatory agent,vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotic promoting factor, enzymatic agent,angiogenic factor, anti-angiogenic factor, hormone, vitamin, mineral,nutraceutical, cytokine, chemokine, probiotic, coagulant,anti-coagulant, phage, prodrug, prebiotic, blood sugar stabilizer,smooth muscle cell activator, epinephrine, adrenaline, neurotoxin,neuro-muscular toxin, Botulinum toxin type A, microbial cell orcomponent thereof, or virus or component thereof. In one embodiment5330, the at least one biological remodeling agent includes one or moreof a blood cell, chondrocyte, endothelial cell, hepatocyte,keratinocyte, myocyte, osteoblast, osteoclast, osteocyte, mesenchymalcell, stem cell, progenitor cell, or fibroblast.

In one embodiment 5340, the at least one biological remodeling agentincludes one or more of calcium phosphate, albumin, cytokine, pegylatedcytokine, bone, cartilage, globulin, fibrin, thrombin,glutaraldehyde-crosslinked pericardium, hide powder, hyaluronic acid,hydroxylapatite, keratin, ligament, nitinol, nucleic acid polymers,polyethylene, polylethylene glycol, polyethylene glycol diacrylate,polyethylene terephthalate fiber, polyglycol, polylactate,polytetrafluoroethylene, polylactic acid, polyglycolic acid,polycaprolactone, PURAMATRIX™ self-assembly peptide hydrogel fibers,linear aliphatic polyester, tendon, fibrinogen, hyaluronate, chitin,chitosan, methylcellulose, alginate, hyaluronic acid, agarose,cellulose, polyaldehyde gluronate, Factor XIII, Factor XII, silk, nylon,collagen, silicone, polyurethane, ceramic powder, elastin, pectin, wax,glycosaminoglycan, poly(α-hydroxyacid), selectin, glutaraldehyde,hydrophobic non-glycosylated protein, hydrogel, peptide hydrogel, orgelatin.

In one embodiment 5350, the at least one biological remodeling agentincludes one or more of Type I collagen, Type II collagen, Type IIIcollagen, Type VII collagen, Type X collagen, elastin fibers, or solubleelastin.

As indicated in FIG. 54, a method 5400 comprises receiving 5410 one ormore signals that include information related to accepting inputassociated with at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions; receiving 5420 one or more signals that includeinformation related to evaluating the at least one biological tissue forone or more indicators of tissue formation or growth; and processing5430 the information related to the input associated with at least oneparameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue and the informationrelated to the evaluating the at least one biological tissue. In oneembodiment 5440, the evaluating at least one biological tissue for oneor more indicators includes evaluating at least one of an assay, image,or gross assessment of the at least one biological tissue prior to,during, or subsequent to at least one administration of one or morefrozen particle compositions.

In one embodiment 5450, the assay includes at least one technique thatincludes spectroscopy, microscopy, electrochemical detection,polynucleotide detection, histological examination, biopsy analysis,fluorescence resonance energy transfer, electron transfer, enzyme assay,electrical conductivity, isoelectric focusing, chromatography,immunoprecipitation, immunoseparation, aptamer binding, filtration,electrophoresis, immunoassay, or radioactive assay. In one embodiment5460, the image includes at least one image acquired by one or more ofoptical coherence tomography, computer-assisted tomography scan,computed tomography, magnetic resonance imaging, positron-emissiontomography scan, ultrasound, x-ray, electrical-impedance monitoring,microscopy, spectrometry, flow cytommetry, radioisotope imaging, thermalimaging, multiphoton calcium-imaging, photography, or in silicogeneration.

As indicated in FIG. 55, the one or more indicators 5510 of tissueformation or growth include at least one of: cell migration, cellattachment, cell retention, cell differentiation, cell proliferation,apoptosis, diffusion of materials, angiogenesis, nucleic acidexpression, protein translation, protein modification, carbohydrateproduction, carbohydrate secretion, fat production, fat secretion, orprotein secretion.

In one embodiment 5520, the input associated with at least one parameterof at least partially constructing or at least partially reconstructingthe at least one biological tissue includes one or more of: constitutionof the one or more frozen particle compositions, formulation of the oneor more frozen particle compositions, size of the one or more frozenparticle compositions, shape of the one or more frozen particlecompositions, angle of administration of the one or more frozen particlecompositions, velocity of administration of the one or more frozenparticle compositions, quantity of frozen particle compositionsadministered, rate of administration of more than one frozen particlecomposition, spatial location for administration of one or more frozenparticle compositions, temporal location for administration of one ormore frozen particle compositions, method of administration of one ormore frozen particle compositions, timing of administration of one ormore frozen particle compositions, modulation of administration of oneor more frozen particle compositions, deposition of one or more frozenparticle compositions, or rate of deposition of at least one agent.

In one embodiment 5530, the receiving one or more signals includesreceiving one or more signals associated with selection of one or morefrozen particle compositions for administration. In one embodiment 5540,the receiving one or more signals includes receiving one or more signalsassociated with the selection of at least one of a biological remodelingagent, adhesive agent, abrasive, therapeutic agent, reinforcement agent,or explosive material associated with the one or more frozen particlecompositions.

As indicated in FIG. 56, in one embodiment 5610, the administering oneor more frozen particle compositions includes administering the one ormore frozen particle compositions to at least one substrate. In oneembodiment 5620, the at least one substrate includes one or more of acell, tissue, organ, structure, or device. In one embodiment 5630, theone or more frozen particle compositions include one or more frozenparticles including at least one of hydrogen oxide, nitrogen, oxygen,air, helium, neon, argon, xenon, chlorine, bromine, carbon dioxide,acetone, ethyl acetate, dimethyl sulfoxide, dimethyl formamide, dioxane,tetrahydrofuran, acetronitrile, acetic acid, n-butanol, isopropanol,n-propanol, hexamethylphosphorotriamide, perfluorohydrocarbon, methanol,ethanol, tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia,benzene, carbon tetrachloride, acetonitrile, hexane, dichloromethane,methylene chloride, carboxylic acid, saline, standard saline citrate,methane, toluene, chloroform, polyethylene glycol, acetic acid, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,standard saline citrate, HEPES-buffered saline, dextrose, glucose,methane, or diethyl ether.

In one embodiment 5640, the at least one agent includes one or more ofan adhesive agent, therapeutic agent, reinforcement agent, abrasive,explosive material, or biological remodeling agent. In one embodiment5650, the adhesive agent, therapeutic agent, reinforcement agent,abrasive, explosive material, or biological remodeling agent issubstantially in the form of at least one of an organic or inorganicsmall molecule, clathrate or caged compound, protocell, coacervate,microsphere, Janus particle, proteinoid, laminate, helical rod,liposome, macroscopic tube, niosome, sphingosome, toroid, vesiculartube, vesicle, small unilamellar vesicle, large unilamellar vesicle,large multilamellar vesicle, multivesicular vesicle, lipid layer, lipidbilayer, micelle, organelle, cell, membrane, nucleic acid, peptide,polypeptide, protein, oligosaccharide, polysaccharide, glycopeptide,glycolipid, sphingolipid, glycosphingolipid, glycoprotein,peptidoglycan, lipid, carbohydrate, metalloprotein, proteoglycan,chromosome, cell nucleus, acid, base, buffer, protic solvent, aproticsolvent, nitric oxide, nitric oxide synthase, nitrous oxide, amino acid,micelle, polymer, bone cement, copolymer, cell receptor, adhesionmolecule, cytokine, chemokine, immunoglobulin, antibody, antigen,platelet, extracellular matrix, blood, plasma, cell ligand, zwitterionicmaterial, cationic material, oligonucleotide, nanotube, or piloxymer.

As indicated in FIG. 57, the one or more explosive materials 5710include at least one of a carbonate, carbon dioxide, nitroglycerine,acid, base, epoxy, acrylic polymer or copolymer, acrylamide polymer orcopolymer, urethane, hypoxyapatite, or reactive metal. In one embodiment5720, the at least one adhesive agent includes one or more of an acrylicpolymer or copolymer, acrylamide polymer or copolymer polymer orcopolymer, acrylamide polymer or copolymer, polyacrylic acid, epoxy,urethane, gum arabic, polyester, polyhydroxyalkanoate, poly(L-lacticacid), polyglycolide, polylactic acid, polyether, polyol,polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, hydroxyapatite,polyelectrolyte, maleic polyelectrolyte, cellulose, resilin,cyanoacrylate, isocyanate, 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate, butyl-2-cyanoacrylate,methyl 2-cyanoacrylate, polyisohexylcyanoacrylate, fibrin, thrombin,fibrinogen, hyaluronate, chitin, Factor XIII, Factor XII, silk, nylon,collagen, glycosaminoglycan, selectin, polyurethane, methacrylate, orpolysulfide, polyanhydride, polydioxanone, poly-p-dioxanone, silicone,albumin, glutaraldehyde, polyethylene glycol, or gelatin. In oneembodiment 5730, the one or more reinforcement agents include one ormore of polyaramid, vinylester matrix, metal, ceramic, fiberglass,cellulose, broad carbide, aromatic polyamide, nylon, silk, rayon,acetate, modacrylic, olefin, acrylic, polyester, aromatic polyester,poly-lactic acid, vinyon, saran, spandex, vinalon, aromatic nylon,vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell, orlon,zylon, high-performance polyethylene, polypyridobenzimidazole, vectran,acrylonitrile rubber, glass, copper, iron, steel, sodium, potassium,calcium, zinc, manganese, carbon, magnesium, silicon, silica, frozenhydrogen oxide ice, plant matter, animal matter, or mineral matter.

In one embodiment 5740, the therapeutic agent includes at least one ofan anti-tumor agent, antimicrobial agent, anti-viral agent, analgesic,antiseptic, anesthetic, diagnostic agent, anti-inflammatory agent,vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotic promoting factor, enzymatic agent,angiogenic factor, anti-angiogenic factor, hormone, vitamin, mineral,nutraceutical, cytokine, chemokine, probiotic, coagulant,anti-coagulant, phage, prodrug, prebiotic, blood sugar stabilizer,smooth muscle cell activator, epinephrine, adrenaline, neurotoxin,neuro-muscular toxin, Botulinum toxin type A, microbial cell orcomponent thereof, or virus or component thereof.

In one embodiment 5810, the at least one biological remodeling agentincludes one or more of a blood cell, chondrocyte, endothelial cell,hepatocyte, keratinocyte, myocyte, osteoblast, osteoclast, osteocyte,mesenchymal cell, stem cell, progenitor cell, or fibroblast. In oneembodiment 5820, the at least one biological remodeling agent includesone or more of calcium phosphate, albumin, cytokine, pegylated cytokine,bone, cartilage, globulin, fibrin, thrombin, glutaraldehyde-crosslinkedpericardium, hide powder, hyaluronic acid, hydroxylapatite, keratin,ligament, nitinol, nucleic acid polymers, polyethylene, polylethyleneglycol, polyethylene glycol diacrylate, polyethylene terephthalatefiber, polyglycol, polylactate, polytetrafluoroethylene, polylacticacid, polyglycolic acid, polycaprolactone, PURAMATRIX™ self-assemblypeptide hydrogel fibers, linear aliphatic polyester, tendon, fibrinogen,hyaluronate, chitin, chitosan, methylcellulose, alginate, hyaluronicacid, agarose, cellulose, polyaldehyde gluronate, Factor XIII, FactorXII, silk, nylon, collagen, silicone, polyurethane, ceramic powder,elastin, pectin, wax, glycosaminoglycan, poly(α-hydroxyacid), selectin,glutaraldehyde, hydrophobic non-glycosylated protein, hydrogel, peptidehydrogel, or gelatin. In one embodiment 5830, the at least onebiological remodeling agent includes one or more of Type I collagen,Type II collagen, Type III collagen, Type VII collagen, Type X collagen,elastin fibers, or soluble elastin.

In one embodiment 5840, the at least one biological remodeling agent isincluded as part of a carrier that assists in synthesis or activation ofthe at least one biological remodeling agent.

As indicated in FIG. 59, a method 5900 comprises comparing information5910 regarding at least one parameter for at least partiallyconstructing or at least partially reconstructing at least onebiological tissue of a subject by administering one or more frozenparticle compositions to the at least one subject and informationregarding at least one clinical outcome following receipt by the atleast one subject of one or more frozen particle compositions; andproviding output information 5920. In one embodiment 5930, the outputinformation is based on the comparison. In one embodiment 5940, themethod further comprises determining at least one statisticalcorrelation. In one embodiment 5950, the method further comprisescounting the occurrence of at least one clinical outcome. In oneembodiment 5960, the information regarding at least one parameter of atleast partially constructing or at least partially reconstructing atleast one biological tissue of a subject includes information regardingquantity of cells or tissue at least partially constructed or at leastpartially reconstructed. In one embodiment 5970, the informationregarding at least one parameter of at least partially constructing orat least partially reconstructing at least one biological tissue of asubject includes information regarding at least one cellular or tissuesource. In one embodiment 5980, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of a subject includesinformation regarding at least one abnormal cellular or tissue source.In one embodiment 5990, the information regarding at least one parameterof at least partially constructing or at least partially reconstructingat least one biological tissue of a subject includes informationregarding at least one type of cell or tissue.

As indicated in FIG. 60, the at least one agent 6010 includes at leastone agent including at least one adhesive agent, abrasive, reinforcementagent, therapeutic agent, biological remodeling agent, or explosivematerial. In one embodiment 6020, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of a subject includesinformation regarding at least one dimension of at least one agentdeposited. In one embodiment 6030, the information regarding at leastone parameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least one subjectincludes information regarding at least one dimension of at least onedepth, width, or breadth of cellular, tissue, or other material removalor destruction. In one embodiment 6040, the information regarding atleast one clinical outcome following receipt by the at least one subjectof one or more frozen particle compositions includes informationregarding two or more subjects with one or more common attributes.

In one embodiment 6050, the one or more common attributes include one ormore of genetic attributes, mental attributes, proteomic attributes,phenotypic attributes, or psychological attributes. In one embodiment6060, the one or more common attributes include one or more of height,weight, medical diagnosis, familial background, results on one or moremedical tests, ethnic background, body mass index, age, presence orabsence of at least one disease or condition, species, ethnicity, race,allergies, gender, thickness of tissue, blood vessel condition, hair orfur condition, skin condition, tissue condition, muscle condition, organcondition, nerve condition, brain condition, presence or absence of atleast one biological, chemical, or therapeutic agent in the subject,pregnancy status, lactation status, genetic profile, proteomic profile,partial or whole genetic sequence, partial or whole proteomic sequence,medical condition, medical history, or blood condition.

As indicated in FIG. 61, the output information 6110 includes at leastone of a response signal, comparison code, comparison plot, diagnosticcode, treatment code, test code, code indicative of at least onetreatment received, code indicative of at least one prescribed treatmentstep, code indicative of at least one vaccination administered, codeindicative of at least one therapeutic agent administered, codeindicative of at least one diagnostic agent administered, codeindicative of at least one interaction of an administered agent and atleast one biological or chemical agent in the subject; a code indicativeof at least one dispertion or location of at least one administeredagent; code indicative of at least one detection material administered;code indicative of the depth of penetration of an administered agent,code indicative of the depth of deposition of an administered agent, ora code indicative of the condition of at least one location of anadministered frozen particle composition.

In one embodiment 6120, receipt by the at least one subject of one ormore frozen particle compositions is pursuant to at least one clinicaltrial. In one embodiment 6130, the method further comprises determiningat least one correlation before the administration of the one or morefrozen particle compositions to the at least one subject.

In one embodiment 6140, the method further comprises creating at leastone inclusion criterion and at least one exclusion criterion for aclinical trial involving the one or more frozen particle compositions.In one embodiment 6150, the method further comprises suggesting theinclusion of one or more of the at least one subject in at least oneclinical trial. In one embodiment 6160, the method further comprisessuggesting the exclusion of one or more of the at least one subject inat least one clinical trial.

As indicated in FIG. 62, the method further comprising using one or moreof the at least one correlation 6210 to predict at least one clinicaloutcome regarding at least one second subject. In one embodiment 6220,the at least one second subject has not received the one or more frozenparticle compositions. In one embodiment 6230, the method furthercomprises predicting at least one clinical outcome involving the atleast one second subject, wherein the at least one second subject is aplurality of people; and segregating subject identifiers associated withthe plurality of people in reference to the predicted at least oneclinical outcome. In one embodiment 6240, the method further comprisesdetermining the eligibility of the at least one second subject for theat least one clinical trial.

In one embodiment 6250, the one or more frozen particle compositionsinclude one or more frozen particles including at least one of hydrogenoxide, nitrogen, oxygen, air, helium, neon, argon, xenon, chlorine,bromine, carbon dioxide, acetone, ethyl acetate, dimethyl sulfoxide,dimethyl formamide, dioxane, tetrahydrofuran, acetronitrile, aceticacid, n-butanol, isopropanol, n-propanol, hexamethylphosphorotriamide,perfluorohydrocarbon, methanol, ethanol, tert-butyl alcohol, formicacid, hydrogen fluoride, ammonia, benzene, carbon tetrachloride,acetonitrile, hexane, dichloromethane, methylene chloride, carboxylicacid, saline, standard saline citrate, methane, toluene, chloroform,polyethylene glycol, acetic acid, Ringer's solution, lactated Ringer'ssolution, Hartmann's solution, acetated Ringer's solution, phosphatebuffered solution, TRIS-buffered saline solution, Hank's balanced saltsolution, Earle's balanced salt solution, standard saline citrate,HEPES-buffered saline, dextrose, glucose, methane, or diethyl ether.

As indicated in FIG. 63, the at least one agent 6310 includes one ormore of an adhesive agent, therapeutic agent, reinforcement agent,abrasive, explosive material, or biological remodeling agent. In oneembodiment 6320, the adhesive agent, therapeutic agent, reinforcementagent, abrasive, explosive material, or biological remodeling agent issubstantially in the form of at least one of an organic or inorganicsmall molecule, clathrate or caged compound, protocell, coacervate,microsphere, Janus particle, proteinoid, laminate, helical rod,liposome, macroscopic tube, niosome, sphingosome, toroid, vesiculartube, vesicle, small unilamellar vesicle, large unilamellar vesicle,large multilamellar vesicle, multivesicular vesicle, lipid layer, lipidbilayer, micelle, organelle, cell, membrane, nucleic acid, peptide,polypeptide, protein, oligosaccharide, polysaccharide, glycopeptide,glycolipid, sphingolipid, glycosphingolipid, glycoprotein,peptidoglycan, lipid, carbohydrate, metalloprotein, proteoglycan,chromosome, cell nucleus, acid, base, buffer, protic solvent, aproticsolvent, nitric oxide, nitric oxide synthase, nitrous oxide, amino acid,micelle, polymer, bone cement, copolymer, cell receptor, adhesionmolecule, cytokine, chemokine, immunoglobulin, antibody, antigen,platelet, extracellular matrix, blood, plasma, cell ligand, zwitterionicmaterial, cationic material, oligonucleotide, nanotube, or piloxymer. Inone embodiment 6330, the one or more explosive materials include atleast one of a carbonate, carbon dioxide, nitroglycerine, acid, base,epoxy, acrylic polymer or copolymer, acrylamide polymer or copolymer,urethane, hypoxyapatite, or reactive metal. In one embodiment 6340, theat least one adhesive agent includes one or more of an acrylic polymeror copolymer, acrylamide polymer or copolymer polymer or copolymer,acrylamide polymer or copolymer, polyacrylic acid, epoxy, urethane, gumarabic, polyester, polyhydroxyalkanoate, poly(L-lactic acid),polyglycolide, polylactic acid, polyether, polyol, polyvinylpyrrolidone,pyroxylin, polymethylacrylate-isobutene-monoisopropylmaleate, siloxanepolymer, polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, hydroxyapatite,polyelectrolyte, maleic polyelectrolyte, cellulose, resilin,cyanoacrylate, isocyanate, 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate, butyl-2-cyanoacrylate,methyl 2-cyanoacrylate, polyisohexylcyanoacrylate, fibrin, thrombin,fibrinogen, hyaluronate, chitin, Factor XIII, Factor XII, silk, nylon,collagen, glycosaminoglycan, selectin, polyurethane, methacrylate, orpolysulfide, polyanhydride, polydioxanone, poly-p-dioxanone, silicone,albumin, glutaraldehyde, polyethylene glycol, or gelatin.

As indicated in FIG. 64, the one or more reinforcement agents 6410include one or more of polyaramid, vinylester matrix, metal, ceramic,fiberglass, cellulose, broad carbide, aromatic polyamide, nylon, silk,rayon, acetate, modacrylic, olefin, acrylic, polyester, aromaticpolyester, poly-lactic acid, vinyon, saran, spandex, vinalon, aromaticnylon, vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell,orlon, zylon, high-performance polyethylene, polypyridobenzimidazole,vectran, acrylonitrile rubber, glass, copper, iron, steel, sodium,potassium, calcium, zinc, manganese, carbon, magnesium, silicon, silica,frozen hydrogen oxide ice, plant matter, animal matter, or mineralmatter.

In one embodiment 6420, the therapeutic agent includes at least one ofan anti-tumor agent, antimicrobial agent, anti-viral agent, analgesic,antiseptic, anesthetic, diagnostic agent, anti-inflammatory agent,vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotic promoting factor, enzymatic agent,angiogenic factor, anti-angiogenic factor, hormone, vitamin, mineral,nutraceutical, cytokine, chemokine, probiotic, coagulant,anti-coagulant, phage, prodrug, prebiotic, blood sugar stabilizer,smooth muscle cell activator, epinephrine, adrenaline, neurotoxin,neuro-muscular toxin, Botulinum toxin type A, microbial cell orcomponent thereof, or virus or component thereof. In one embodiment6430, the at least one biological remodeling agent includes one or moreof a blood cell, chondrocyte, endothelial cell, hepatocyte,keratinocyte, myocyte, osteoblast, osteoclast, osteocyte, mesenchymalcell, stem cell, progenitor cell, or fibroblast.

As indicated in FIG. 65, the at least one biological remodeling agent6510 includes one or more of calcium phosphate, albumin, cytokine,pegylated cytokine, bone, cartilage, globulin, fibrin, thrombin,glutaraldehyde-crosslinked pericardium, hide powder, hyaluronic acid,hydroxylapatite, keratin, ligament, nitinol, nucleic acid polymers,polyethylene, polylethylene glycol, polyethylene glycol diacrylate,polyethylene terephthalate fiber, polyglycol, polylactate,polytetrafluoroethylene, polylactic acid, polyglycolic acid,polycaprolactone, PURAMATRIX™ self-assembly peptide hydrogel fibers,linear aliphatic polyester, tendon, fibrinogen, hyaluronate, chitin,chitosan, methylcellulose, alginate, hyaluronic acid, agarose,cellulose, polyaldehyde gluronate, Factor XIII, Factor XII, silk, nylon,collagen, silicone, polyurethane, ceramic powder, elastin, pectin, wax,glycosaminoglycan, poly(α-hydroxyacid), selectin, glutaraldehyde,hydrophobic non-glycosylated protein, hydrogel, peptide hydrogel, orgelatin. In one embodiment 6520, the at least one biological remodelingagent includes one or more of Type I collagen, Type II collagen, TypeIII collagen, Type VII collagen, Type X collagen, elastin fibers, orsoluble elastin. In one embodiment 6530, the at least one biologicalremodeling agent is included as part of a carrier that assists insynthesis or activation of the at least one biological remodeling agent.

As indicated in FIG. 66, a method 6600 of predicting a clinical outcomeof one or more frozen particle composition treatments for at least onefirst subject, comprises determining 6610 a similarity or adissimilarity in information regarding at least one parameter for atleast partially constructing or at least partially reconstructing atleast one biological tissue of at least one first subject byadministering one or more frozen particle compositions to the at leastone first subject with information regarding at least one parameter ofat least partially constructing or at least partially reconstructing atleast one biological tissue of at least one second subject, wherein theat least one second subject 6620 attained a clinical outcome followingreceipt of one or more frozen particle compositions; and providingoutput information 6630.

In one embodiment 6640, providing output information is based on thedetermination. In one embodiment 6650, the information regarding atleast one parameter of at least partially constructing or at leastpartially reconstructing at least one biological tissue of at leastsecond subject includes information regarding quantity of cells ortissue at least partially constructed or at least partiallyreconstructed. In one embodiment 6660, the information regarding atleast one parameter of at least partially constructing or at leastpartially reconstructing at least one biological tissue of at least onefirst subject includes information regarding at least one cellular ortissue source. In one embodiment 6670, the information regarding atleast one parameter of at least partially constructing or at leastpartially reconstructing at least one biological tissue of at least onefirst subject includes information regarding at least one abnormalcellular or tissue source.

As indicated in FIG. 67, the information 6710 regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least one firstsubject includes information regarding at least one type of cell ortissue. In one embodiment 6720, the information regarding at least oneparameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least one secondsubject includes information regarding at least one type of cell ortissue. In one embodiment 6730, the at least one agent includes one ormore of an adhesive agent, abrasive, reinforcement agent, therapeuticagent, biological remodeling agent, or explosive material. In oneembodiment 6740, the information regarding at least one parameter of atleast partially constructing or at least partially reconstructing atleast one biological tissue of at least one first subject includesinformation regarding at least one dimension of at least one agentdeposited.

In one embodiment 6750, the information regarding at least one parameterof at least partially constructing or at least partially reconstructingat least one biological tissue of at least one second subject includesinformation regarding at least one dimension of at least one agentdeposited. In one embodiment 6760, the information regarding at leastone parameter of at least partially constructing or at least partiallyreconstructing at least one biological tissue of at least one secondsubject includes information regarding at least one dimension of atleast one depth, width, or breadth of cellular, tissue, or othermaterial removal or destruction. In one embodiment 6770, the informationregarding at least one parameter of at least partially constructing orat least partially reconstructing at least one biological tissue of atleast one first subject includes information regarding at least onedimension of at least one depth, width, or breadth of cellular, tissue,or other material removal or destruction.

As indicated in FIG. 68, the information 6810 regarding at least oneclinical outcome following receipt by the at least one second subject ofone or more frozen particle compositions includes information regardingtwo or more subjects with one or more common attributes. In oneembodiment 6820, the one or more common attributes include one or moreof genetic attributes, mental attributes, proteomic attributes,phenotypic attributes, or psychological attributes. In one embodiment6830, the one or more common attributes include one or more of height,weight, medical diagnosis, familial background, results on one or moremedical tests, ethnic background, body mass index, age, presence orabsence of at least one disease or condition, species, ethnicity, race,allergies, gender, thickness of tissue, blood vessel condition, hair orfur condition, skin condition, tissue condition, muscle condition, organcondition, nerve condition, brain condition, presence or absence of atleast one biological, chemical, or therapeutic agent in the subject,pregnancy status, lactation status, genetic profile, proteomic profile,partial or whole genetic sequence, partial or whole proteomic sequence,medical condition, medical history, or blood condition. In oneembodiment 6840, the output information includes at least one of aresponse signal, comparison code, comparison plot, diagnostic code,treatment code, test code, code indicative of at least one treatmentreceived, code indicative of at least one prescribed treatment step,code indicative of at least one vaccination administered, codeindicative of at least one therapeutic agent administered, codeindicative of at least one diagnostic agent administered, codeindicative of at least one interaction of an administered agent and atleast one biological or chemical agent in the subject; a code indicativeof at least one dispersion or location of at least one administeredagent; code indicative of at least one detection material administered;code indicative of the depth of penetration of an administered agent,code indicative of the depth of deposition of an administered agent, ora code indicative of the condition of at least one location of anadministered frozen particle composition.

As indicated in FIG. 69, in one embodiment 6910, receipt by the at leastone second subject of one or more frozen particle compositions ispursuant to at least one clinical trial. In one embodiment 6920, themethod further comprises determining at least one correlation before theadministration of the one or more frozen particle compositions to the atleast one first subject. In one embodiment 6930, the method furthercomprises creating at least one inclusion criterion and at least oneexclusion criterion for a clinical trial involving the one or morefrozen particle compositions. In one embodiment 6940, the method furthercomprises suggesting the inclusion of one or more of the at least onefirst subject in at least one clinical trial. In one embodiment 6950,the method further comprises suggesting the exclusion of one or more ofthe at least one first subject in at least one clinical trial.

In one embodiment 6960, the method further comprises using one or moreof the at least one correlation to predict at least one clinical outcomeregarding at least one second subject. In one embodiment 6970, the atleast one second subject has not received the one or more frozenparticle compositions. In one embodiment 6980, the method furthercomprises predicting at least one clinical outcome involving the atleast one second subject, wherein the at least one second subject is aplurality of people; and segregating subject identifiers associated withthe plurality of people in reference to the predicted at least oneclinical outcome.

As indicated in FIG. 70, in one embodiment 7010, the one or more frozenparticle compositions include one or more frozen particles including atleast one of hydrogen oxide, nitrogen, oxygen, air, helium, neon, argon,xenon, chlorine, bromine, carbon dioxide, acetone, ethyl acetate,dimethyl sulfoxide, dimethyl formamide, dioxane, tetrahydrofuran,acetronitrile, acetic acid, n-butanol, isopropanol, n-propanol,hexamethylphosphorotriamide, perfluorohydrocarbon, methanol, ethanol,tert-butyl alcohol, formic acid, hydrogen fluoride, ammonia, benzene,carbon tetrachloride, acetonitrile, hexane, dichloromethane, methylenechloride, carboxylic acid, saline, standard saline citrate, methane,toluene, chloroform, polyethylene glycol, acetic acid, Ringer'ssolution, lactated Ringer's solution, Hartmann's solution, acetatedRinger's solution, phosphate buffered solution, TRIS-buffered salinesolution, Hank's balanced salt solution, Earle's balanced salt solution,standard saline citrate, HEPES-buffered saline, dextrose, glucose,methane, or diethyl ether.

In one embodiment 7020, the one or more frozen particle compositionsinclude one or more of an adhesive agent, therapeutic agent,reinforcement agent, abrasive, explosive material, or biologicalremodeling agent. In one embodiment 7030, the adhesive agent,therapeutic agent, reinforcement agent, abrasive, explosive material, orbiological remodeling agent is substantially in the form of at least oneof an organic or inorganic small molecule, clathrate or caged compound,protocell, coacervate, microsphere, Janus particle, proteinoid,laminate, helical rod, liposome, macroscopic tube, niosome, sphingosome,toroid, vesicular tube, vesicle, small unilamellar vesicle, largeunilamellar vesicle, large multilamellar vesicle, multivesicularvesicle, lipid layer, lipid bilayer, micelle, organelle, cell, membrane,nucleic acid, peptide, polypeptide, protein, oligosaccharide,polysaccharide, glycopeptide, glycolipid, sphingolipid,glycosphingolipid, glycoprotein, peptidoglycan, lipid, carbohydrate,metalloprotein, proteoglycan, chromosome, cell nucleus, acid, base,buffer, protic solvent, aprotic solvent, nitric oxide, nitric oxidesynthase, nitrous oxide, amino acid, micelle, polymer, bone cement,copolymer, cell receptor, adhesion molecule, cytokine, chemokine,immunoglobulin, antibody, antigen, platelet, extracellular matrix,blood, plasma, cell ligand, zwitterionic material, cationic material,oligonucleotide, nanotube, or piloxymer.

In one embodiment 7040, the one or more explosive materials include atleast one of a carbonate, carbon dioxide, nitroglycerine, acid, base,epoxy, acrylic polymer or copolymer, acrylamide polymer or copolymer,urethane, hypoxyapatite, or reactive metal.

As indicated in FIG. 71, the at least one adhesive agent 7110 includesone or more of an acrylic polymer or copolymer, acrylamide polymer orcopolymer polymer or copolymer, acrylamide polymer or copolymer,polyacrylic acid, epoxy, urethane, gum arabic, polyester,polyhydroxyalkanoate, poly(L-lactic acid), polyglycolide, polylacticacid, polyether, polyol, polyvinylpyrrolidone, pyroxylin,polymethylacrylate-isobutene-monoisopropylmaleate, siloxane polymer,polylactic-co-glycolic-acid, poly-3-hydroxybutyrate,poly-4-hydroxybutyrate, polyhydroxyvalerate, polydydroxyhexanoate,polydyroxyoctanoate, polycaprolactone, poly(e-caprolactone), sialylLewis^(x), heme group, hemoglobin, healon, carboxymethylcellulose,hydroxyapatite, silicone, cadherin, integrin, hydroxyapatite,polyelectrolyte, maleic polyelectrolyte, cellulose, resilin,cyanoacrylate, isocyanate, 2-octyl cyanoacrylate,2-butyl-n-cyanoacrylate, n-butyl-2-cyanoacrylate, butyl-2-cyanoacrylate,methyl 2-cyanoacrylate, polyisohexylcyanoacrylate, fibrin, thrombin,fibrinogen, hyaluronate, chitin, Factor XIII, Factor XII, silk, nylon,collagen, glycosaminoglycan, selectin, polyurethane, methacrylate, orpolysulfide, polyanhydride, polydioxanone, poly-p-dioxanone, silicone,albumin, glutaraldehyde, polyethylene glycol, or gelatin.

In one embodiment 7120, the one or more reinforcement agents include oneor more of polyaramid, vinylester matrix, metal, ceramic, fiberglass,cellulose, broad carbide, aromatic polyamide, nylon, silk, rayon,acetate, modacrylic, olefin, acrylic, polyester, aromatic polyester,poly-lactic acid, vinyon, saran, spandex, vinalon, aromatic nylon,vinylidene chloride, modal, polybenzimidazole, sulfur, lyocell, orlon,zylon, high-performance polyethylene, polypyridobenzimidazole, vectran,acrylonitrile rubber, glass, copper, iron, steel, sodium, potassium,calcium, zinc, manganese, carbon, magnesium, silicon, silica, frozenhydrogen oxide ice, plant matter, animal matter, or mineral matter.

In one embodiment 7130, the therapeutic agent includes at least one ofan anti-tumor agent, antimicrobial agent, anti-viral agent, analgesic,antiseptic, anesthetic, diagnostic agent, anti-inflammatory agent,vaccine, cell growth inhibitor, cell growth promoter, immunogen,antigen, radioactive agent, apoptotic promoting factor, enzymatic agent,angiogenic factor, anti-angiogenic factor, hormone, vitamin, mineral,nutraceutical, cytokine, chemokine, probiotic, coagulant,anti-coagulant, phage, prodrug, prebiotic, blood sugar stabilizer,smooth muscle cell activator, epinephrine, adrenaline, neurotoxin,neuro-muscular toxin, Botulinum toxin type A, microbial cell orcomponent thereof, or virus or component thereof.

As indicated in FIG. 72, the at least one biological remodeling agent7210 includes one or more of a blood cell, chondrocyte, endothelialcell, hepatocyte, keratinocyte, myocyte, osteoblast, osteoclast,osteocyte, mesenchymal cell, stem cell, progenitor cell, or fibroblast.In one embodiment 7220, the at least one biological remodeling agentincludes one or more of calcium phosphate, albumin, cytokine, pegylatedcytokine, bone, cartilage, globulin, fibrin, thrombin,glutaraldehyde-crosslinked pericardium, hide powder, hyaluronic acid,hydroxylapatite, keratin, ligament, nitinol, nucleic acid polymers,polyethylene, polylethylene glycol, polyethylene glycol diacrylate,polyethylene terephthalate fiber, polyglycol, polylactate,polytetrafluoroethylene, polylactic acid, polyglycolic acid,polycaprolactone, PURAMATRIX™ self-assembly peptide hydrogel fibers,linear aliphatic polyester, tendon, fibrinogen, hyaluronate, chitin,chitosan, methylcellulose, alginate, hyaluronic acid, agarose,cellulose, polyaldehyde gluronate, Factor XIII, Factor XII, silk, nylon,collagen, silicone, polyurethane, ceramic powder, elastin, pectin, wax,glycosaminoglycan, poly(α-hydroxyacid), selectin, glutaraldehyde,hydrophobic non-glycosylated protein, hydrogel, peptide hydrogel, orgelatin. In one embodiment 7230, the at least one biological remodelingagent includes one or more of Type I collagen, Type II collagen, TypeIII collagen, Type VII collagen, Type X collagen, elastin fibers, orsoluble elastin. In one embodiment 7240, the at least one biologicalremodeling agent is included as part of a carrier that assists insynthesis or activation of the at least one biological remodeling agent.

As indicated in FIG. 73, a system 7300 comprises at least one computingdevice 7310; one or more instructions 7340 that when executed on the atleast one computing device cause the at least one computing device toreceive a first input associated with a first possible dataset, thefirst possible dataset including data representative of one or moreparameters for administering one or more frozen particle compositions.In one embodiment 7350, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to compare a value associatedwith the first possible dataset with a second dataset including valuesof at least one predictive parameter for administering one or morefrozen particle compositions. In one embodiment 7320, the at least onecomputing device includes one or more of a desktop computer, workstationcomputer, or computing system. In one embodiment 7330, the at least onecomputing system includes one or more of a cluster of processors, anetworked computer, a tablet personal computer, a laptop computer, amobile device, a mobile telephone, or a personal digital assistantcomputer.

As indicated in FIG. 74, the system further comprises one or moreinstructions 7460 that when executed on the at least one computingdevice cause the at least one computing device to determine a graphicalillustration of the second possible dataset.

In one embodiment 7410, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to determine from the comparisonat least one parameter for administering one or more frozen particlecompositions. In one embodiment 7420, the system further comprises oneor more instructions that when executed on the at least one computingdevice cause the at least one computing device to generate at least oneresponse based on the determination. In one embodiment 7430, the systemfurther comprises one or more instructions that when executed on the atleast one computing device cause the at least one computing device toaccess the first possible dataset in response to the first input.

In one embodiment 7440, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to generate the first possibledataset in response to the first input.

In one embodiment 7450, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to determine a graphicalillustration of the first possible dataset.

As indicated in FIG. 75, a system 7510 comprises at least one computingdevice 7520; one or more instructions 7560 that when executed on the atleast one computing device cause the at least one computing device toreceive a first input associated with a first possible dataset, thefirst possible dataset including data representative of one or morecharacteristics of at least one biological tissue or organ to be atleast partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions. In oneembodiment 7570, the system further comprises one or more instructionsthat when executed on the at least one computing device cause the atleast one computing device to compare a value associated with the firstpossible dataset with a second dataset including values of at least onepredictive characteristic of at least one biological tissue or organ tobe at least partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions.

In one embodiment 7530, the at least one computing device includes oneor more of a desktop computer, workstation computer, or computingsystem. In one embodiment 7540, the at least one computing systemincludes one or more of a cluster of processors, a networked computer, atablet personal computer, a laptop computer, a mobile device, a mobiletelephone, or a personal digital assistant computer. In one embodiment7550, the at least one computing device is configured to communicatewith at least one apparatus for selecting or generating one or morefrozen particle compositions.

As indicated in FIG. 76, the system further comprises one or moreinstructions 7610, that when executed on the at least one computingdevice cause the at least one computing device to determine a graphicalillustration of the second possible dataset. In one embodiment 7620, thesystem further comprises one or more instructions that when executed onthe at least one computing device cause the at least one computingdevice to determine from the comparison at least one characteristic ofthe at least one biological tissue or organ to be at least partiallyconstructed or at least partially reconstructed by administering one ormore frozen particle compositions. In one embodiment 7630, the systemfurther comprises one or more instructions that when executed on the atleast one computing device cause the at least one computing device togenerate at least one response based on the determination.

In one embodiment 7640, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to access the first possibledataset in response to the first input. In one embodiment 7650, thesystem further comprises one or more instructions that when executed onthe at least one computing device cause the at least one computingdevice to generate the first possible dataset in response to the firstinput. In one embodiment 7660, the system further comprises one or moreinstructions that when executed on the at least one computing devicecause the at least one computing device to determine a graphicalillustration of the first possible dataset.

As indicated in FIG. 77, a system 7700 comprises a signal-bearing medium7710 bearing one or more instructions 7720 for accepting a first inputassociated with at least one characteristic of at least one biologicaltissue to be at least partially constructed or at least partiallyreconstructed by administering one or more frozen particle compositions;one or more instructions 7730 for accepting a second input associatedwith at least one characteristic of at least one parameter of at leastpartially constructing or at least partially reconstructing the at leastone biological tissue by administering one or more frozen particlecompositions that include at least one agent; and one or moreinstructions 7740 for processing results of the first input and thesecond input. In one embodiment 7750, the system further comprising oneor more instructions for displaying results of the processing.

In one embodiment 7760, the system further comprises one or moreinstructions for transmitting one or more signals that includeinformation related to the processing results of the first input and thesecond input. In one embodiment 7770, the system further comprises oneor more instructions for administering one or more frozen particlecompositions that include at least one agent including: biologicalremodeling agent, therapeutic agent, adhesive agent, abrasive,reinforcement agent, or explosive material. In one embodiment, thesystem 7780 further comprises one or more instructions for evaluatingthe at least one biological tissue for one or more indicators relatingto one or more of: deposition of at least one agent, tissue formation,or tissue growth.

In one embodiment 7790, the signal-bearing medium includes acomputer-readable medium. In one embodiment 7795, the signal-bearingmedium includes a recordable medium. In one embodiment 7797, thesignal-bearing medium includes a communications medium.

As indicated in FIG. 78, a computer program product 7800 comprises asignal-bearing medium 7810 bearing one or more instructions 7820 foraccepting a first input associated with at least one characteristic ofat least one biological tissue to be at least partially constructed orat least partially reconstructed by administering one or more frozenparticle compositions; one or more instructions 7830 for accepting asecond input associated with at least one characteristic of at least oneparameter of at least partially constructing or at least partiallyreconstructing the at least one biological tissue by administering oneor more frozen particle compositions that include at least one agent;and one or more instructions 7840 for processing results of the firstinput and the second input.

In one embodiment 7850, the computer program product further comprisesone or more instructions for displaying results of the processing. Inone embodiment 7860, the computer program product further comprises oneor more instructions for transmitting one or more signals that includeinformation related to the processing results of the first input and thesecond input. In one embodiment 7870, the computer program productfurther comprises one or more instructions for administering one or morefrozen particle compositions that include at least one agent includingbiological remodeling agent, therapeutic agent, adhesive agent,abrasive, reinforcement agent, or explosive material.

In one embodiment 7880, the computer program product further comprisesone or more instructions for evaluating the at least one biologicaltissue for one or more indicators relating to one or more of depositionof at least one agent, tissue formation, or tissue growth.

In one embodiment 7890, the signal-bearing medium includes acomputer-readable medium. In one embodiment 7895, the signal-bearingmedium includes a recordable medium. In one embodiment 7897, thesignal-bearing medium includes a communications medium.

As indicated in FIG. 79, a system 7900 comprises circuitry 7910 foraccepting a first input associated with at least one characteristic ofat least one biological tissue to be at least partially constructed orat least partially reconstructed by administering one or more frozenparticle compositions; circuitry 7920 for accepting a second inputassociated with at least one characteristic of at least one parameter ofat least partially constructing or at least partially reconstructing theat least one biological tissue by administering one or more frozenparticle compositions that include at least one agent; and circuitry7930 for processing results of the first input and the second input. Inone embodiment 7940, the system further comprises circuitry fordisplaying results of the processing. In one embodiment 7950, the systemfurther comprises circuitry for transmitting one or more signals thatinclude information related to the processing results of the first inputand the second input. In one embodiment 7960, the system furthercomprises circuitry for administering one or more frozen particlecompositions that include at least one agent including at least onebiological remodeling agent, therapeutic agent, adhesive agent,abrasive, reinforcement agent, or explosive material. In one embodiment7970, the system further comprises circuitry for evaluating the at leastone biological tissue for one or more indicators relating to one or moreof deposition of at least one agent, tissue formation, or tissue growth.

As indicated in FIG. 80, a system 8000 comprises at least at least onecomputer program 8010, configured with a computer-readable medium, foruse with at least one computer system and wherein the computer programincludes a plurality of instructions including but not limited to: oneor more instructions 8020 for accepting a first input associated with atleast one characteristic of at least one biological tissue to be atleast partially constructed or at least partially reconstructed byadministering one or more frozen particle compositions; one or moreinstructions 8030 for accepting a second input associated with at leastone characteristic of at least one parameter of at least partiallyconstructing or at least partially reconstructing the at least onebiological tissue by administering one or more frozen particlecompositions that include at least one agent; and one or moreinstructions 8040 for processing results of the first input and thesecond input.

In one embodiment 8050, the system further comprises one or moreinstructions for displaying results of the processing. In one embodiment8060, the system further comprises one or more instructions fortransmitting one or more signals that include information related to theprocessing results of the first input and the second input.

In one embodiment 8070, the system further comprises one or moreinstructions for administering one or more frozen particle compositionsthat include at least one agent including biological remodeling agent,therapeutic agent, adhesive agent, abrasive, reinforcement agent, orexplosive material. In one embodiment 8080, the system further comprisesone or more instructions for evaluating the at least one biologicaltissue for one or more indicators relating to one or more of depositionof at least one agent, tissue formation, or tissue growth.

As indicated in FIG. 81, the system further comprises at least onecomputing device 8110. In one embodiment 8120, the at least onecomputing device is configured to communicate with at least one printingdevice, at least one imaging device, or at least one input device.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein can beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, those skilled in the art willrecognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat the mechanisms of the subject matter described herein are capableof being distributed as a program product in a variety of forms, andthat an illustrative embodiment of the subject matter described hereinapplies regardless of the particular type of signal bearing medium usedto actually carry out the distribution. Examples of a signal bearingmedium include, but are not limited to, the following: a recordable typemedium such as a floppy disk, a hard disk drive, a Compact Disc (CD), aDigital Video Disk (DVD), a digital tape, a computer memory, etc.; and atransmission type medium such as a digital and/or an analogcommunication medium (e.g., a fiber optic cable, a waveguide, a wiredcommunications link, a wireless communication link (e.g., transmitter,receiver, transmission logic, reception logic, etc.), etc.).

For any of the various aspects and embodiments disclosed herein, one ormore kits can be developed with the components described herein. In oneembodiment, a kit includes one or more frozen particle compositions asdescribed herein. In one embodiment, a kit includes one or more frozenparticle compositions and at least one therapeutic agent as disclosedherein. In one embodiment, a kit includes one or more frozen particlecompositions and one or more reinforcement agents. In one embodiment, akit includes one or more frozen particle compositions and one or moreexplosive materials.

PROPHETIC EXAMPLES Example 1 Compositions and Methods of Making FrozenParticles

Frozen particle compositions suitable for various embodiments describedherein can be produced by controlling the pressure and temperature ofhydrogen oxide that is introduced as a liquid, gas or frozen. Frozenparticle compositions, including frozen hydrogen oxide ice Ic, areproduced by cooling small hydrogen oxide droplets (˜6 μm diameter) below−38° C. (See e.g., Murray, et al., Phys. Chem. Chem. Phys. vol. 8, pp.186-192 (2006), which is incorporated herein by reference). Emulsions of30-40% by weight of distilled and de-ionized hydrogen oxide in paraffinoil (Fisher Scientific) are agitated to produce hydrogen oxide dropletsof mean diameters ranging from 5 to 35 μm as determined by opticalmicroscopy. The droplets are cooled to −100° C. at a rate of 10° C./minby using a cryostat cooled with liquid nitrogen and containing a heaterand temperature controller. Freezing liquid droplets with a mediandiameter of 5.6 μm or smaller can provide approximately 80% frozen iceIc and approximately 20% frozen ice Ih. Following the procedures ofMurray et al, selective production of ice Ic in pellet form producesquantities suitable for use in various embodiments described herein.

Frozen particles generated in this manner are utilized for abrasion ofat least one biological tissue, including but not limited to skin. Thefrozen particle composition is administered to at least one biologicaltissue by, for example, accelerating, ejecting, or propelling the frozenparticles by way of a carrier gas under pressure (e.g., air, carbondioxide, nitrogen) through a tube, or other device directed toward atleast one biological tissue, such as skin. Microdermabrasion,microscissuining, or other surface abrasion techniques are carried outin a similar fashion.

Example 2 Compositions and Methods of Making Frozen Particles

Frozen particles, including frozen hydrogen oxide ice Ic, are producedby depositing hydrogen oxide vapor onto a copper plate held at lowtemperatures in vacuo. Purified (deionized) hydrogen oxide is added to avessel at approximately 25° C. and the hydrogen oxide vapor is condensedonto a metal plate held at approximately −196° C. in vacuo. Thedeposited amorphous ice is heated (at 10° C./min) to approximately −93°C. and is converted to crystalline cubic ice (ice Ic). Ice Ic is stablewhen stored under liquid nitrogen (See e.g., Johari, et al., J. Phys.Chem, vol. 94, pp. 1212-1214 (1990), which is incorporated herein byreference). An example of an apparatus that is used to produce frozenhydrogen oxide ice Ic is described in Hallbrucker et al (J. Phys. Chem.,vol. 93, pp. 4986-4990 (1989), which is incorporated herein byreference).

Example 3 Compositions and Methods of Making Frozen Particles

Frozen hydrogen oxide ice Ic particles are produced from small hydrogenoxide droplets in an example of a “pelletizer” apparatus similar tothose described by, for example, U.S. Pat. No. 4,617,064; U.S. Pat. No.6,306,119, which are incorporated herein by reference. Frozen hydrogenoxide ice Ic particles are formed by spraying hydrogen oxide droplets ofthe desired size into a cooling chamber filled with a cold inert gasmaintained at the desired temperature, for example, nitrogen gasmaintained at approximately −100° C. to promote formation of ice Ic.Spray droplet size is maintained by variation of nozzle/orifice size andhydrogen oxide pressure to yield droplet diameters ranging fromnanometers to centimeters. Frozen hydrogen oxide ice Ic, ice Ih,amorphous low density ice, amorphous high density ice, and other formsare produced by controlling the temperature and pressure of the coolingchamber. Cubic hydrogen oxide ice Ic particles are formed in a step-wiseprocess, by maintaining the chamber at a very low temperature(approximately −196° C.) with increased pressure, which first promotesformation of amorphous hydrogen oxide ice. Next, the chamber is heatedto approximately −93° C., which results in transformation to cubichydrogen oxide ice (ice Ic) particles.

The hydrogen oxide ice particles are propelled into a delivery system(such as tubing and nozzle) by nitrogen gas under pressure. The deliverysystem is maintained at the appropriate temperature for preservation ofthe hydrogen oxide particle structure, (e.g., approximately −93° C. forice Ic structure).

Example 4 Compositions and Methods of Making Frozen Carbon DioxideParticles

Carbon dioxide frozen particles are produced from small carbon dioxidedroplets in a “pelletizer” similar to those described by, for example,U.S. Pat. No. 4,617,064; and U.S. Pat. No. 6,306,119; each of which isincorporated herein by reference. Carbon dioxide frozen particles areformed by spraying liquid carbon dioxide droplets into a cooling chambermaintained at low temperatures (e.g., approximately −100° C.). Dropletsize is regulated by varying nozzle or orifice size, and pressure.Carbon dioxide droplet diameters range, for example, from nanometers tocentimeters. The frozen carbon dioxide particles are propelled into adelivery system (e.g., tubing and nozzle) by carrier gas, (e.g., air ornitrogen) under pressure. The carbon dioxide particles are maintainedwhile in the delivery system at the appropriate temperature, (e.g.,approximately −100° C.). Frozen carbon dioxide particles sublimate, ortransition to a gas phase, at approximately −78.5° C. and 1 atmpressure.

Example 5 Compositions and Methods of Making Frozen DMSO Particles

Dimethyl sulfoxide (DMSO) frozen particles are produced from DMSOdroplets, for example, in a “pelletizer” apparatus similar to thosedescribed by, for example, U.S. Pat. No. 4,617,064; U.S. Pat. No.6,306,119, which are incorporated herein by reference. DMSO frozenparticles are formed from spraying liquid DMSO droplets of the desiredsize into a cooling chamber that is maintained at low temperature, forexample, less than approximately 18.5° C. Droplet size is regulated byvarying nozzle or orifice size, and pressure, with compressed air as acarrier gas. Droplet size can be regulated by varying nozzle or orificesize, and DMSO pressure. DMSO droplet diameters range, for example, fromnanometers to centimeters. The DMSO frozen particles are propelled by acarrier gas (e.g., air or nitrogen) under pressure to enter a deliverysystem (e.g., tubing and nozzle). In order to preserve DMSO particlestructure, the delivery system is maintained at low temperature (e.g.,less than approximately 18.5° C.).

Example 6 Methods of Assessment or Selection of Frozen Particles

According to various embodiments described herein, at least one frozenparticle is made by lowering the temperature of liquid droplets of aselected material. Droplet and particle sizes are measured by imaging aspray or particle stream upon a background screen. The background screenis illuminated with a short pulse of light, for example, from aninfrared laser beam (at approximately 805 nm), which is capable ofpulsing at frequencies of approximately 1000 Hz.

A digital camera captures high resolution images of the droplets orparticles. High-speed, real-time particle sizing software analyses theimages to assess the diameter distribution for the particles and todetermine the shape. The diameter of each droplet is determinedautomatically by referencing the number of dark pixels in the dropletimage to the pixel area of a calibration circle. Droplet diametersbetween approximately 100 μm (±3.2%) and approximately 2000 μm (±0.03%)were measured with 95% confidence (See e.g., Ireland et al., 6thASME-JSME Thermal Engineering Joint Conference (2003), which isincorporated herein by reference). Instruments, computer programs andprotocols for measuring particle and droplet size are available, forexample, from Oxford Lasers, Shirley, Mass. (e.g., world wide web atoxfordlasers.com, which is incorporated herein by reference).

Example 7 Methods of Assessment or Selection of Frozen Particles

According to various embodiments described herein, at least one frozenparticle is made by lowering the temperature of liquid droplets of aselected material. Droplet and particle sizes are measured by laserdiffraction. Laser diffraction based particle size analysis relies onparticles passing through a laser beam and scattering light at an anglethat is directly related to their size. As particle size decreases, theobserved scattering angle increases logarithmically. Scatteringintensity is also dependent on particle size, and decreases withdecreasing particle volume. Thus, large particles scatter light atnarrow angles with high intensity whereas small particles scatter atwider angles but with low intensity. Laser diffraction is used for thenon-destructive analysis of wet or dry samples, to measure particles inthe size range 0.02 to 2000 micrometers (e.g., world wide web atchemie.de/articles/e/61205/, which is incorporated herein by reference).A laser diffraction instrument, protocols and analysis software areavailable, for example, from Malvern Instruments Ltd. (Malvern,Worcestershire, WR14 1XZ United Kingdom).

Example 8 Compositions and Methods of Making Frozen Particles Includinga Reinforcement Agent

One or more reinforcement agents are added to the frozen particlesduring the formation process. Among other things, reinforcement agentscan increase the strength of frozen particles (e.g., increase themodulus of rupture of ice) and decrease the deformation of frozenparticles (e.g., decrease the beam deflection of ice). As indicated inTable A below, glass fibers present at 9% (wt./vol.), for example,increase the modulus of rupture of ice by approximately 7-fold relativeto ice derived from unreinforced hydrogen oxide ice (See e.g., Kingery,Science, vol. 134, pp. 164-168 (1960), which is incorporated herein byreference).

TABLE A Strength of fresh ice with sawdust and Fiberglass, respectively,added. Additions were % wt./vol. (Kingery, Ibid). Modulus of rupture(kg/cm²) Addition (%) Sawdust (−17° C.) Fiberglass (−20° C.) 0 22.5 24.10.8 22.7 24.0 2.5 35 65.4 9.0 60 161 14.0 66.7 N/A

As indicated in FIG. 5, the beam deflection is less than 0.005 inchesfor hydrogen oxide ice that is reinforced with approximately 9.0% glassfibers and increases over time for hydrogen oxide ice that is reinforcedwith approximately 0.8% glass fibers (Kingery, Ibid). Furthermore,hydrogen oxide ice with approximately 9% (w/v) of glass fibers is notdeformed over 23 hours under an applied force of approximately 24.5in·lbs. As described in Kingery, et al, and as indicated in FIG. 5, beamdeflection of hydrogen oxide ice with approximately 0.8% glass fibers isapproximately 0.16 inches after 23 hours under 25.3 in·lbs. of force.Likewise, as indicated in FIG. 5, and according to Kingery et al,hydrogen oxide ice without reinforcement agents is deformedapproximately 0.05 inches after 4 hours under approximately 26.6 in·lbs.of force. Additionally, aluminum and silica carbonate particles can bemixed at various volume fractions and co-milled under an argonatmosphere to produce nanocrystalline composites as reinforcement agentsfor frozen particle compositions. (See e.g., Kamrani, et al., PowderMet. vol. 50, pp. 276-282(7) (2007), which is incorporated herein byreference).

Example 9 Compositions and Methods of Making Frozen Particles

Frozen particles (e.g., carbon dioxide, DMSO, gelatin) are reinforced byincorporating one or more reinforcement agents, including but notlimited to silica beads, fiberglass, polyethylene glycol, kaolin, orwood fibers.

Silica beads approximately 1 micrometer in diameter are mixed withhydrogen oxide at approximately 0° C. to make volume fractions includingthe approximate ranges, but not limited to, 0, 0.004, 0.04, 0.15, 0.29,0.49 and 0.63 volume fraction. The volume fractions, or one or moreparticular volume fraction, are frozen in, for example, a cylindricalmold, at low temperatures (e.g., approximately −10° C.). Unconfinedcoaxial compression tests are used to determine the maximum stress (alsoknown as the failure point) of the one or more frozen particles atdefined temperatures and strain rates (See e.g., Yasui et al, Geophys.Res. Lett., vol. 35, L12206, (2008), which is incorporated herein byreference).

As indicated in FIG. 6, maximum stress values (MPa) increase formixtures with an increased volume fraction of silica beads relative tothe maximum stress for unreinforced hydrogen oxide ice. (See e.g., Yasuiet al, Ibid.) φ=silica volume fraction

The strength of specific frozen particles is altered by varying thecomposition of frozen particle mixtures containing one or morereinforcement agents. For example, Table B indicates the frozen particlestrength of frozen particles including hydrogen oxide, DMSO, carbondioxide, and gelatin, which contain at least one reinforcement agent. Asindicated, the reinforced frozen particles exhibited increased strengthcompared to their unreinforced counterparts. As indicated in Table B,frozen particles containing at least one reinforcement agent at thevolume fractions shown in the table displayed maximal strength incompression tests. (See also, FIGS. 5 and 6, as well as Table A hereinfor hydrogen oxide frozen particle strength).

TABLE B Frozen particles and reinforcement agents leading to increasedparticle strength Particle Base Fiber Glass Saw Dust Silica Beads PEGKaolin Ice 0.15* 0.14 0.63 ND 0.15 DMSO 0.15 0.14 0.63 ND 0.15 carbon0.15 0.14 0.63 ND 0.15 dioxide gelatin 0.15 0.14 0.63 ND 0.15 Volumefraction for reinforcement agents in frozen particle base materials isgiven. ND = Not Determined. (Yasui, et al.)

Example 10 Vaccine Compositions and Methods of Making Frozen Particles

As described herein, immunization of a subject with a vaccine isaccomplished by way of introduction of the vaccine through, for example,subcutaneous, transcutaneous or intramuscular administration. (See e.g.,Berzofsky et al, Nat. Rev. Immunol. vol. 1, pp. 209-219, (2001), whichis incorporated herein by reference). Non-limiting examples of frozenparticle vaccines are described herein, and include one or moreimmunogens. The immunogen therapeutic compositions are made, forexample, in solution or as a solid in suspension or as a colloid createdfrom, for example, buffered solutions (e.g., phosphate, citrate,lactate, pyruvate or an organic acid buffer) that optimize the stabilityand immunogenicity of the vaccine.

Storage stability of vaccines depends upon many factors, includingvaccine formulation and storage temperature. For example, an influenzasubunit vaccine formulated with trehalose, and Hepes buffered saline, isstable at room temperature for approximately 26 weeks (See e.g., Amorijet al, Pharm. Res. vol. 25, pp. 1256-1273 (2008), which is incorporatedherein by reference).

Vaccines with adjuvants such as: N-acetylmuramyl-l-alanyl-d-isoglutamine, also called muramyl dipeptide (MDP) ormonophosphoryl lipid A (MPL) elicit enhanced cellular and humoralimmunity (See e.g., Aguilar et al Vaccine vol. 25, pp. 3752-62 (2007),which is incorporated herein by reference).

Furthermore, stable genetic transformation and vaccination of intactplant cells has been achievable by particle bombardment processes (Seee.g., Klein et al PNAS vol. 85, pp. 8502-8505 (1988), and Klein et alBioTech vol. 24, pp. 384-386 (1992); each of which is incorporatedherein by reference).

One or more hydrogen oxide frozen particle vaccine compositions,including, for example, one or more buffers, one or more immunogens(e.g., viral protein subunits) and one or more adjuvants, as a solutionor suspension, are made by spraying the compositions through an orificeor nozzle. Each vaccine composition is propelled by a pressurized gas(e.g., compressed air) into a cooling chamber maintained at, forexample, approximately −40° C.

The vaccine composition is delivered to at least one biological tissueof a subject, for example, by propelling the particles via a carrier gasunder pressure (e.g., air, carbon dioxide, nitrogen) through a tubedirected toward at least one biological tissue (including but notlimited to plant callus, plant leaves, plant roots, plant stems,vasculature, lymphatic, lymph node, epidermis, subcutaneous,intramuscular, oral, nasal, pulmonary, intraperitoneal or rectaltissue).

Alternatively, the vaccine composition is delivered to at least onebiological tissue of a subject, for example, by first forming the frozenparticle vaccine compositions through spraying composition droplets intoa cryogen bath (e.g., liquid nitrogen). The frozen particle compositionsare subsequently delivered to at least one biological tissue by flashboiling liquid nitrogen, and propelling the frozen particle compositionsthrough a tube or barrel, for example, to at least one biological tissueof a subject.

Frozen particle vaccine compositions containing one or morereinforcement agents (e.g., silica beads) and of the appropriate sizeand shape (e.g., bullet, spheroid, high aspect ratio shape) penetratethe at least one biological tissue when propelled to high velocity by acarrier gas. In one non-limiting example, a vaccine compositionapproximately 20-70 ηm in size penetrates the epidermis when thecomposition is accelerated to high speed with a powder jet injector(PowerJect, PowerJect Pharmaceuticals) (Amorij et al, Ibid.).

Similarly, one group found that using the Bio-Rad HELIOS Gene Gun® andmicroparticle-delivery of pCMV-S DNA vaccination in mice resulted ingreater numbers of animals achieving immunity than those receivingintramuscular injection. (See, e.g., Conn et al, Bio-Rad Tech Note 2726,available on the worldwide web atbio-rad.com/LifeScience/pdf/Bulletin_(—)2726.pdf, accessed Feb. 12,2009, the content of which is incorporated herein by reference.)

For plant leaves, a high rate of infection with a Potyviridae virus wasobtained by another group using the Bio-Rad HELIOS Gene Gun® andmicroparticle-delivery of the virus. (See, e.g., Kekarainen andValkonen, Bio-Rad Tech Note 2531, available on the worldwide web atbio-rad.com/LifeScience/pdf/Bulletin_(—)2531.pdf, accessed Feb. 12,2009, the content of which is incorporated herein by reference.) Theauthors found optimal infection rates in plant leaves under a heliumpressure of 150 psi or 200 psi, at a distance of 0 cm from the deliverydevice to the tissue. (Id. at page 2).

Example 11 Vaccine Compositions and Methods of Making Frozen Particles

Frozen particle vaccine compositions containing multiple immunogens, forexample, toxoids (chemically modified toxins) from bacteria such asClostridium tetani, Cornybacterium diphtheriae or Bordetella pertussis,stimulate immunity to multiple bacteria or toxins in a single vaccinecomposition.

Alternatively, multiple distinct immunogens, proteins, or peptides thatare derived from a single pathogen are combined in a single frozenparticle vaccine composition that immunizes a subject against apathogenic virus or bacteria that mutates frequently. For example,multiple hemagglutinin or neuraminidase proteins, (e.g., H1N1, H3N2)from different viral strains (e.g., A/New Caledonia/H1N1, orA/Wellington/H3N2) or viral species of influenza (e.g., influenza A orinfluenza B) are combined in a single frozen particle vaccinecomposition and provides immunity to multiple strains or species. (Seee.g., Kamps et al, Influenza Report, pp. 127-149 (2006); world wide webat influenzareport.com/ir/vaccines; each of which is incorporated hereinby reference).

Alternatively, frozen particle vaccine compositions including one ormore immunogens, antigens or proteins (e.g., influenza A/NewCaledonia/(H1N1)) are combined with one or more frozen particle vaccinecompositions containing one or more different antigens (e.g., influenzaB/Shanghai or influenza A/Wellington/(H3N2)). Such a frozen particlevaccine composition combination provides immunity against seasonalvariants of viral pathogens.

In one non-limiting example, combinations of frozen particle vaccinecompositions including specific antigens from selected influenzavariants or strains target a seasonal flu epidemic. (Kamps et al, Ibid.)Combination of frozen particle compositions are made containing one ormore different antigens or epitopes, wherein the one or more differentantigens or epitopes are derived from mutant or variant HIV proteinsthat evolve during HIV infection (See e.g., Berzofsky et al, J. Clin.Inv. vol. 114, pp. 450-462 (2004)). Such combination compositionsimmunize a subject against existing HIV mutants and anticipate theemergence of new HIV mutants or variants.

Alternatively, one or more frozen particle vaccine compositions aredelivered to one or more mucosal tissues (e.g., nasal, oral, rectal,pulmonary) via propulsion using a “pellet gun,” via inhalation, oringestion by a subject. For example, an influenza vaccine lyophilizedand delivered nasally as spherical particles, approximately 26.9 μm(mean diameter), induces mucosal (e.g., nasal IgA response) and systemicimmunity (e.g., serum antibody response) to influenza virus (See e.g.,Garmise et al, AAPS PharmSciTech. vol. 8:E81 (2007); Huang et al,Vaccine. vol. 23(6), pp. 794-801 (2004); each of which is incorporatedherein by reference).

Alternatively, the one or more frozen particle vaccine compositions aredelivered to one or more pulmonary surfaces of the subject viapropulsion by way of a “pellet gun,” by using flash boiled liquidnitrogen as a propellant, or by inhalation. Frozen particle influenzavaccine compositions administered to one or more pulmonary surfaces of asubject elicit mucosal and systemic humoral, as well as cell-mediatedimmune responses to influenza (See e.g., Amorij et al Vaccine. vol. 25,pp. 8707-8717 (2007), which is incorporated herein by reference).

Example 12 Compositions and Methods of Making Frozen Particles

Frozen particle compositions of the appropriate size and shape,including botulinum toxin, an optimal buffer (e.g., Hepes buffer), oneor more stabilizing agents, and one or more reinforcement agents areadministered through the skin of a subject to neuromuscular junctions.Botulinum toxin inhibits acetylcholine release, which blocks synapseformation, and temporarily paralyzes the corresponding musculature.

Frozen particle compositions containing a recommended dose of botulinumtoxin (See e.g., Borodic, U.S. Pat. No. 5,183,462, which is incorporatedherein by reference), and at least one reinforcement agent (e.g.,polymer) are administered to skeletal muscles using a delivery systemderived from inkjet printer technology (See e.g., world wide web aten.wikipedia.org/wiki/Inkjet Printer) that sprays picoliter quantitiesof the frozen particle compositions at high velocity (e.g., 50 m/sec)toward the skin of the subject. Botulinum toxin is typicallyadministered by subcutaneous injection (generally with a 26 gaugehypodermic needle). Botulinum toxin is approved by the FDA for therapyof strabismus (crossed-eyes), blepharospasm (uncontrolled blinking), andother facial nerve disorders including hemifacial spasm. It is alsoapproved for treatment of cervical dystonia and glabellar (frown) lines(See e.g., Jankovic, J. Neurol. Neurosurg. Psychiatry vol. 75, pp.951-957 (2004), which is incorporated herein by reference).

In addition, botulinum toxin is included in the treatment of focal orsegmental dystonia (e.g., oromandibular-facial-lingual dystonia,laryngeal dystonia, limb dystonia). Dystonias are neurological disorderswith repetitive and patterned contractions of muscles that causeabnormal movements and postures. For example, cervical dystonia subjectsare injected with, for example, approximately 100 I.U of botulinumtoxin, distributed over 3-5 injection sites, spaced 5-15 mm apart,across the length of the sternomastoid muscle. (Borodic, Ibid.)

Frozen particle compositions containing botulinum toxin are administeredto facial muscles that underlie frown lines, wrinkles, and “crow'sfeet.” For example, botulinum toxin is targeted to: 1) the corrugatorand procerus muscles to treat vertical glabellar eyebrow furrows; 2) tomultiple sites in the frontalis muscle to eliminate horizontal lines inthe forehead; or 3) to the lateral orbicularis oculi to treat crow'sfeet.

Frozen particle compositions containing an optimal dose of botulinumtoxin (e.g., 0.2-0.4 I.U./kg) are administered over the length of aspecific facial muscle (e.g., orbicularis oculi) by use of a deliverysystem with an inkjet nozzle. As described herein, picoliter volumes ofone or more frozen particle compositions are sprayed at a velocity thatachieves a desired or predetermined depth (for example, 5-8 mm; Borodic,Ibid.). The velocity is also altered according to the size, shape, andconstituents of the frozen particle composition.

Example 13 Methods of Administering Frozen Particle TherapeuticCompositions

Frozen hydrogen oxide particles of ice Ic form and at least onetherapeutic agent or at least one diagnostic agent are formulated fortreatment of hematological cancers (e.g., leukemia or lymphoma) or solidtumors (e.g., carcinoma, sarcoma). For example, at least one ofneo-adjuvant therapy, adjuvant therapy, chemotherapy, antibody therapy,or immunotherapy are employed

In one non-limiting embodiment, frozen hydrogen oxide particles are usedfor adjuvant therapy of cancers treated with surgery such as coloncancer, lung cancer, and breast cancer. At least one frozen particlehydrogen oxide therapeutic composition containing one or morereinforcement agents (e.g., silica beads, Kevlar®), one or more buffers,one or more stabilizing agents (e.g., one or more saccharides), and oneor more cancer therapeutic agents (such as one or more chemotherapydrugs, antibodies, biological agents (e.g., antibodies, cytokines orpeptides), or one or more chemotherapeutic agents) are administered toan area proximal to a region of at least one biological tissue where atumor is present or believed to be present. Optionally, resection of atleast a part of a tumor can be performed, with or without additionaladministration of the at least one frozen particle therapeuticcomposition.

The at least one frozen particle therapeutic composition is administeredin such a manner as described herein, that allows for desired depth ofpenetration of the at least one biological tissue. In one embodiment,the at least one frozen particle therapeutic composition is administeredto a depth that allows for at least one of intracellular orintercellular delivery. For example, the at least one frozen particletherapeutic composition is administered to a depth that allows fordelivery to at least one of epithelium, endothelium, vasculature,lymphatic vessels, lymph nodes or mucosa.

Specifically, if metastasis is present or believed to be present in thesubject, administration of the at least one frozen particle therapeuticcomposition is delivered to such region of metastases ormicro-metastases are believed to be present.

Frozen particle hydrogen oxide therapeutic compositions provided as anadjuvant therapy are administered by spraying at least one compositionunder pressure with a carrier gas through a nozzle designed to uniformlydistribute particles over at least one biological tissue at sufficientvelocity to penetrate the tissue exposed during tumor resection.

Advanced colon cancer (e.g., stage II, III) is treated surgically byremoval of sections of colon containing tumor with margins of “normal”colon tissue and often includes removal of associated lymph nodes andmesentery (colectomy). Standard adjuvant therapy following surgery issystemic administration of a combination of chemotherapy drugs (e.g.,5-fluorouracil, leucovorin or oxaliplatin (FOLFOX)), (See e.g., Wolpinet al, CA Cancer J. Clin. vol. 57, pp. 168-185 (2007)). Systemic FOLFOXadjuvant therapy is associated with significant toxicities includinggastrointestinal toxicity, neutropenia and neurotoxicity (Wolpin et al,Ibid.). Localized in situ delivery of FOLFOX by administration of frozenparticle therapeutic compositions permits delivery of a lower dose.

Administration of at least one frozen particle hydrogen oxidetherapeutic composition containing at least one therapeutic antibodyincludes, for example, bevacizumab (an anti-vascular endothelial growthfactor) or cetuximab (an anti-epidermal growth factor receptor).Bevacizumab and cetuximab both target the tumor-associated vasculatureand tumor cells in the remaining colon sections and the surroundingtissues, mesentery and lymph nodes. Localized administration oftherapeutic antibodies provides sustained protection from recurrence ofcolon tumors at the site of tumor resection and in the surroundingtissues. (Wolpin et al, Ibid.). Following surgery and adjuvant therapywith one or more frozen particle hydrogen oxide therapeuticcompositions, including at least one of one or more chemotherapy drugs,or one or more antibodies, the remaining colon sections are splicedtogether (i.e. anastomosis) or an artificial orifice (i.e. stoma) isinserted to restore a functional colon.

Example 14 Methods of Administering Frozen Particle TherapeuticCompositions

Frozen particle hydrogen oxide therapeutic compositions including one ormore cancer therapeutics or one or more cancer diagnostics are used totreat cancers in distal locations from the primary tumor or initialtumor site treated with surgery or radiation. For example, colon cancercells often metastasize to the liver ((Wolpin et al, Ibid.). At the timeof surgical resection of colon cancer tumors, one or more frozenparticle hydrogen oxide therapeutic compositions including at least onecancer therapeutic, such as one or more cytotoxic drugs (e.g.,fluouracil), antibodies (e.g., cetuximab), radioisotopes conjugated toantibodies (e.g., ¹³¹I-cetuximab), or one or more mixtures of at leastone cytotoxic drug and at least one biological-based therapeutic agentare administered to the liver and surrounding tissues.

Administration of the at least one frozen particle hydrogen oxidetherapeutic composition is accomplished by traditional surgery orlaparoscopic surgery that allows access to the liver (or other organs tobe treated). Administration of at least one frozen particle hydrogenoxide therapeutic composition directly to the liver and the surroundingvasculature allows for intracellular or intercellular penetration andrelease of at least one anti-cancer therapeutic for treatment of anyexisting or suspected colon cancer mestastases or micro-metastases.

As described herein, the at least one frozen particle hydrogen oxidetherapeutic composition including one or more cancer therapeutics areadministered by way of a spraying device. Such a spraying deviceincludes an insulated tube and nozzle, as well as a valve that controlsthe flow of particles. In the case of traditional surgery for tumor ortissue resection, the at least one frozen particle hydrogen oxidetherapeutic composition is sprayed directly onto the target tissue ortissues. Whereas in the case of laparoscopic surgery for tumor or tissueresection, the at least one frozen particle hydrogen oxide therapeuticcomposition is sprayed through a trocar (a hollow tube approximately 10millimeters in diameter).

In certain spraying devices, the at least one frozen particle hydrogenoxide therapeutic composition is administered by way of a carrier gas.The depth of penetration by the at least one therapeutic composition iscontrolled by regulating the carrier gas pressure as well as theconsequent particle velocity. The at least one therapeutic compositionoptionally includes one or more tracer agents or is deliveredsimultaneously with one or more tracer agents. Some non-limitingexamples of tracer agents include dyes, stains or fluorescent compoundsthat mark the tissue area sprayed. The one or more tracer agents canoptionally monitor or provide feedback as to the quantity or quality (inthe case of multiple therapeutic compositions administeredsimultaneously or over time) of the at least one therapeutic compositionadministered to a specific site.

In one embodiment, the at least one frozen particle hydrogen oxidetherapeutic composition including at least one cancer therapeuticfurther includes hematoxylin and eosin stains mixed at a known ratio(e.g., 1:10). Alternatively, a batch of the at least one frozen particlehydrogen oxide therapeutic composition is administered in a mixture orin separate applications frozen particles including hematoxylin andeosin stains. Staining of tissues is visualized by inspection with a lowpower microscope (e.g., dissection microscope) or with a laparoscope,which allows for assessment of the relative quantity or quality of theat least one therapeutic composition administered to the tissue.Staining of the tissues further provides a guide as to the region thatreceived the at least one therapeutic composition.

Example 15 Methods of Administering Frozen Particle TherapeuticCompositions

Frozen particle hydrogen oxide therapeutic compositions including carbondioxide and at least one cancer therapeutic are administered to at leastone tumor or tissue suspected of being cancerous. Upon administration,the frozen particle hydrogen oxide therapeutic compositions penetrateone or more tumor cells, warm to ambient temperature, and undergo rapidsublimation and gaseous expansion of the carbon dioxide. This rapidreaction produces a small explosion that destroys at least one tumorcell as well as one or more adjacent cells. In addition, administrationof the frozen particle therapeutic compositions at low temperatures(e.g., lower than approximately −78.5° C., which is the approximatesublimation temperature for carbon dioxide at 1 atm pressure), freezescells and tissues, causing tumor cell death (See e.g., Vergnon et al,Eur. Respir. J. vol. 28 pp. 200-218 (2006); incorporated herein byreference).

Alternatively, carbon dioxide gas is entrapped in frozen particles byplacing the liquid phase (e.g., hydrogen oxide) under high pressure inthe presence of carbon dioxide gas. (See e.g., U.S. Pat. Nos. 4,289,794;4,289,790; 4,262,029; 5,439,698, each of which is incorporated herein byreference). Administration of the at least one therapeutic compositionis conducted as described herein. In one embodiment, the use of a tubeand nozzle is used that sprays the frozen particle therapeuticcompositions under pressure in a carrier gas (e.g., carbon dioxide,nitrogen). Administration of the at least one therapeutic composition iscarried out as an adjuvant therapy in conjunction with tumor resection,or as an alternative when tumor resection is not favored. For examplelung cancer tumors are generally inoperable when such tumors areadjacent to airways, or infiltrate central airways including thetrachea, main stem bronchi or multiple lung lobes. Additionally,subjects with compromised respiration (e.g., those with lung disease,heart disease or advanced age) are generally not candidates for surgery(See e.g., Spiro et al, Amer. J. Respir. Crit. Care Med., vol. 172, pp.523-529 (2005); which is incorporated herein by reference).

Carbon dioxide frozen particle therapeutic compositions including one ormore chemotherapeutic drugs (e.g., cisplatin, docetaxel, vinorelbine),targeted drugs (e.g., gefitnib, erlotnib), or biological-based agents(e.g., cetuximab, panitumumab, bevacizumab) are administered directlyonto lung cancer tumors. Administration is conducted via endoluminalbronchoscopy or by video-assisted thoracoscopy by means of an insulatedtube and nozzle integral to the endoscopic device. Frozen particlecomposition velocities and spray rate are controlled by a valve betweenthe spray head and the cooling chamber of the “pelletizer.” (See e.g.,U.S. Pat. Nos. 6,306,119, or 6,764,493, each of which is incorporatedherein by reference). Precise localization and administration of thefrozen particle therapeutic compositions are accomplished bybronchoscopy and endoscopy with fluoroscopy used to mark the field(s) ofinterest.

Methods for endoscopic targeting of tumors are described, for example,in Huber et al (Chest vol. 107, pp. 463-470 (1995); which isincorporated herein by reference). Moreover, computed tomography,magnetic resonance imaging, positron emission tomography or othertechniques are used to locate lung cancer tumors.

Frozen particle therapeutic composition administration by usingendoscopic procedures or as an adjuvant therapy in conjunction withtraditional surgery is used for various regions of existing or potentialcarcinogenesis, including mediastinal lymph nodes, vasculature, chestwall and other thoracic sites.

Alternatively, frozen particle therapeutic compositions are deliveredduring traditional surgery for lung cancer and used to treat inoperabletumors remaining following lobectomy, wedge resection, andpneumonectomy, as well as to treat margins of lobe, wedge or lungexcisions to reduce recurrence of lung cancer (See e.g., theworldwideweb at en.wikipedia.org/wiki/Lung_cancer#Surgery; which isincorporated herein by reference). Without wishing to be bound by anyparticular theory, frozen particle carbon dioxide therapeuticcompositions maintained at approximately −80° C. while administered totumors rapidly freeze the tumor cells leading to formation of icecrystals in tumor cells that destroy cell organelles (e.g.,mitochondria) leading to death of the tumor cells. (Vergnon et al,Ibid.)

Similarly, frozen particle therapeutic compositions containing at leastone radioactive element deliver radiation to lung cancer tumor cells.One non-limiting example utilizes frozen particle therapeuticcompositions including ¹⁹²Iridium for irradiating lung tumors thatobstruct major airways. Administration of the frozen particletherapeutic compositions is conducted using an endoscope and a wire toplace the radioactive compositions in at least one lung tumor. Withoutwishing to be bound to any theory, tumor cell irradiation results insingle-stranded DNA breaks that induce apoptosis and reduce rates ofcell division (Vergnon et, Ibid.).

Example 16 Compartmentalized Frozen Particle Therapeutic Compositions

Frozen particles formed in a bullet-shaped mold with hollow cores orcavities that can be filled with therapeutics are useful for deliveringat least one therapeutic agent to a variety of specific tissues, cellsand organ or body locations. Hollow bullet-shaped frozen particles canbe filled with a therapeutic agent such as one or more of an antibody,cytokine, DNA, small interfering RNA, microRNA, aptamer, cytotoxic agent(e.g. a xenobiotic, synthetic, or radioactive agent) that are in aqueoussolution (e.g. sodium phosphate buffer) or form a suspension.Alternatively, hollow frozen bullets can be filled with one or moreliquid or solid polymers or nanoparticles that contain at least onetherapeutic agent (e.g. at least one prodrug) that requires activation.

In one particular embodiment, at least one therapeutic agent is frozenin carbon dioxide. The frozen carbon dioxide/therapeutic agent mixtureor solution is used to fill pre-formed hollow bullet-shaped frozenparticles. In certain embodiments, the hollow bullet-shaped frozenparticles are formed and filled simultaneously. The temperature andpressure of the frozen particles are adjusted according to theparticular constituents and specific parameters of the desired frozenparticle.

Administration of at least one compartmentalized therapeutic frozenparticle composition with a spraying device allows for localizeddelivery of at least one therapeutic agent to specific cells or tissues,such as one or more tumors. In certain embodiments, administration of atleast one compartmentalized therapeutic frozen particle composition isdirected to one or more adjacent, metastatic, or affected tissuesincluding lymph nodes, lymphatic vessels, blood vessels, and organs(e.g. liver, lung, and kidney).

The size, shape or delivery velocity of the at least onecompartmentalized frozen particle composition can be controlled in orderto deliver the at least one particle composition to a desired locationor penetration depth. In certain embodiments, the compartmentalizedfrozen particle composition includes at least one therapeutic agent(e.g. a cytotoxic agent) that is delivered intracellularly,intercellularly, or into the lumen of vasculature, lymphatics, alveoli,bladder, intestine, lungs or into a specific tissue (e.g. endoderm,smooth muscle, skeletal muscle, prostate).

In one example, hollow bullet-shaped frozen particle compositionscontaining a prodrug, such as capecitabine, can be deliveredintracellularly to tumor cells (e.g. colon carcinoma) where capecitabineis metabolized to 5-fluorouracil, an active cytotoxic agent.Administration of at least one frozen particle composition includingcapecitabine specifically to tumor cells and optionally to proximaltissues allows for the potential to increase the therapeutic dose totumor cells, while reducing systemic exposure (which can lead totoxicity and side effects, including angina and myocardial infarction,diarrhea, nausea, neutropenia, anemia and thrombocytopenia).

Alternatively, in one embodiment, intracellular delivery of at least onefrozen particle composition including capecitabine that is encapsulatedin biodegradable polymeric nanoparticles, releases capecitabine in apH-dependent manner. (See for example, Shenoy et al, Pharm. Res. vol.22, pp. 2107-2114 (2005), which is incorporated herein by reference).Since tumor cells generally have a lower pH than non-tumor cells, thecapecitabine is released in higher amounts in the tumor environment.

Alternatively, in one embodiment, at least one frozen particle includescapecitabine and one or more polymeric nanoparticles composed of atleast poly(∈-caplactone) (PCL), a non-pH sensitive polymer that is ableto release capecitabine as the frozen particle melts or sublimates.(See, for example, Shenoy et al, Ibid.).

Example 17 Compartmentalized Frozen Particle Therapeutic CompositionsIncluding Reinforcement Agents for Transdermal Administration

Frozen particle compositions that include at least one therapeutic agentin one or more distinct regions of the particles are useful fortransdermal administration of at least one therapeutic to various layersof the skin or to underlying tissues, organs and structures. Forexample, treatment of certain skin disorders, such as psoriasis, iscurrently limited to topical administration of a therapeutic agent (e.g.coal tar, corticosteroids, vitamin D₃ analogs, or retinoids), systemictreatments (e.g. methotrexate, cyclosporin and retinoids), or UVirradiation (e.g. phototherapy) (See, for example,en.wikipedia/wiki/psoriasis2008, which is incorporated herein byreference). None of these current treatments are fully effective.

In one embodiment, at least one frozen particle composition includingone or more psoriasis therapeutic agents located in one or moregradation layers of concentration, or as a coating on the particle isadministered to the epidermis, dermis or hypodermis layer by controllingspecific parameters, such as particle hardness, size, shape,reinforcement agent, or velocity. For example, frozen particlecompositions including reinforced hydrogen oxide are propelled toward atleast one biological tissue by “flash-boiling” liquid nitrogen to createnitrogen gas and propel the particle compositions by explosive force.The frozen particle compositions are reinforced with plant matter (suchas silk fibers, or collagen fibers), or spun metallic fibers (such astungsten, iron, manganese, carbon, titanium, or steel). The one or morefrozen particle compositions are directed with a hose and nozzle deviceonto psoriatic skin. In addition, the frozen therapeutic particlecompositions can be delivered to the dermis to further impact anypathogenic T cells or cytokines associated with the condition.

In one embodiment, hollow bullet-shaped frozen particle compositionscontaining one or more biological agent, for example etanercept (as ananti-TNF-α therapy), are administered to the dermal layer underlyingareas of psoriatic skin. One or more other therapeutic agents can becombined with the one or more biological agent on the same frozenparticle, or on different frozen particles for administration. Forexample, cytotoxic or cytostatic agents are administered to cellsassociated with psoriasis, including TI cells, T_(H)17 cells, dendriticcells, neutrophils or keratinocytes. (See, for example, Sabat et al,Exp. Derm. vol. 16, pp. 779-798 (2007), which is incorporated herein byreference). For example, therapeutic agents such as anti-CD3,anti-IL-23, anti-IL-17 or cyclosporin are included in one or more frozenparticles to further treat psoriasis in the dermis or epidermis.

Example 18 Compartmentalized Frozen Particle Therapeutic CompositionsIncluding Explosive Materials

Hollow frozen particle compositions including one or more reinforcementagents and hydrogen oxide are filled with solid carbon dioxide. Thehollow frozen particle compositions are useful for destroying,debriding, ablating, or eliminating unwanted cells or tissues such asfat, bone or tumor cells. In one embodiment, the hollow frozen particlecompositions containing a solid carbon dioxide core produces anexplosive force as the particle sublimates or melts duringadministration of the frozen particle compositions. The explosive forcefragments, abrades, or destroys cells or tissues.

At least one sub-group of the frozen particle composition treatmentcourse includes one or more of an antibiotic or other anti-microbialagent; one or more anti-inflammatory drugs; one or more anesthetics oranalgesics; or one or more vasoconstrictors. Targeted delivery of hollowfrozen particle compositions to unwanted cells or tissues is regulatedby controlling, for example, frozen particle hardness, size, shape,reinforcement agents or explosive agents, and velocity. One or morefrozen particle compositions are administered to at least one biologicaltissue by external (e.g. transdermal) methods, or internal (e.g.laparoscopic) methods. In one embodiment, a device (e.g. tube and spraynozzle) is integrated for administration of the one or more frozenparticle compositions.

Compartmentalized frozen particle compositions are useful for destroyingadipocytes or fatty tissue. Present treatments include liposuction,which is performed with a cannula attached to an aspirator that isinserted through small incisions proximal to unwanted fat and thecannula are drawn over the fat to dislodge it and aspirate it (See, forexample, en.wikipedia.org/wiki/Liposuction2008, which is incorporatedherein by reference).

In one embodiment, a tube and spray nozzle is integrated with thecannula for administration of frozen particles containing a solid carbondioxide core and optionally, one or more therapeutic agents. Forexample, the operator sprays frozen particle compositions containingcarbon dioxide toward the adipocytes or fatty tissue in order to removeor destroy the tissue. Next, the treated tissue is aspirated with thecannula.

In one embodiment, a laparoscope can be used with the delivery device toallow visualization of the fatty tissue as well as precise delivery ofthe one or more frozen particle compositions. In certain embodiments,the frozen particle compositions also include lidocaine or ibuprofen inorder to minimize pain and inflammation often associated withliposuction. In certain embodiments, at least one vasoconstrictor, suchas epinephrine, is included in the one or more frozen particles in orderto minimize bleeding. In certain embodiments, antibiotics, such aspenicillin or sulfonamide, are included to reduce infection.

Alternatively, frozen particle compositions including a solid carbondioxide core, one or more antibiotics, analgesics, anti-inflammatorydrugs or vasoconstrictors are delivered transdermally to adipose tissueby spraying the particle compositions as described herein, at theappropriate velocity to penetrate the epidermis, dermis or hypodermis.Following treatment of adipocytes or fatty tissue with the one or morefrozen particles, liposuction is performed to remove the treated cellsor tissues. In one embodiment, adipocytes are selectively treated withminimal effect on the underlying muscle cells, which reduces bruising orbleeding.

Example 19 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Adhesive Agents and One or More BiologicalRemodeling Agents

Frozen particles including hydrogen oxide, carbon dioxide,dimethylsulfoxide or a buffer (e.g. HEPES, Ringer's solution, sodiumcitrate, sodium phosphate, etc.) are formulated with at least oneadhesive agent such as cyanoacrylate, polyethylene glycol polymers oralbumin plus glutaraldehyde.

Frozen particle compositions including at least one adhesive agent areutilized in conjunction with standard methods to achieve hemostasis inpatients undergoing surgery, for example, to repair large blood vesselssuch as the aorta, femoral or carotid arteries. Frozen particlecompositions including bovine albumin and glutaraldehyde (BIOGLUE®,CryoLife, Inc., Kennesaw, Ga.) are utilized, for example, in repair ofan aortic dissection or other blood vessel repair.

Frozen particle compositions including hydrogen oxide, glutaraldehyde,and bovine albumin are produced as described herein at other sections.In an embodiment, various different subsets of frozen particlecompositions are produced, for example, one subset includes frozenhydrogen oxide particles including glutaraldehyde, while another subsetis produced that includes frozen hydrogen oxide particles includingbovine albumin.

In an embodiment, a single set of frozen particle compositions areproduced, for example, including frozen hydrogen oxide particlesincluding both glutaraldehyde and bovine albumin.

In an embodiment, a set of frozen particle compositions are produced,for example, that includes compartmentalized particles wherein bothglutaraldehyde and bovine albumin are present on a particular particle,but each is partially or wholly sequestered in a separate compartment ofthe particular particle. Some examples of compartmentalized frozenparticles are described herein at other sections.

In an embodiment, frozen particles include bovine albumin in a massratio of weight per volume of approximately 5%, approximately 10%,approximately 15%, approximately 20%, approximately 25%, approximately30%, approximately 35%, approximately 40%, approximately 45%,approximately 50%, approximately 55%, approximately 60%, approximately65%, approximately 70%, approximately 75%, or any value therebetween.

In an embodiment, frozen particles include glutaraldehyde in a massratio of weight per volume of approximately 1%, approximately 2%,approximately 3%, approximately 4%, approximately 5%, approximately 6%,approximately 7%, approximately 8%, approximately 9%, approximately 10%,approximately 11%, approximately 12%, approximately 15%, approximately16%, approximately 17%, approximately 18%, approximately 19%,approximately 20%, or any value therebetween.

One or more sets of frozen particle compositions including hydrogenoxide, glutaraldehyde, and/or bovine albumin, as described herein, areadministered to the false lumen of the dissected aorta or other bloodvessel in need of repair, at the distal and proximal anastomotic sites.

In an embodiment, a set of frozen particle compositions including bovinealbumin and glutaraldehyde is administered alone or in conjunction with(sequentially or simultaneously with) other frozen particle compositionsthat optionally include, for example, one or more of at least onetherapeutic agent, at least one reinforcement agent, at least oneexplosive material.

In an embodiment, multiple sets of frozen particle compositions,including bovine albumin and glutaraldehyde on separate particles areadministered simultaneously or sequentially to the biological tissue.These multiple sets of frozen particle compositions are optionallyadministered simultaneously or sequentially with other frozen particlecompositions that include, for example, one or more of at least onetherapeutic agent, at least one reinforcement agent, or at least oneexplosive material.

Depending on the thickness of the blood vessel to be repaired, as wellas other factors, an adhesive layer is administered with a thickness ofapproximately 0.1 mm, approximately 0.2 mm, approximately 0.3 mm,approximately 0.4 mm, approximately 0.5 mm, approximately 0.6 mm,approximately 0.7 mm, approximately 0.8 mm, approximately 0.9 mm,approximately 1.0 mm, approximately 1.5 mm, approximately 2.0 mm,approximately 2.5 mm, approximately 3.0 mm, approximately 3.5 mm,approximately 4.0 mm, approximately 4.5 mm, approximately 5.0 mm,approximately 6.0 mm.

Optionally, subsequent to repair of the distal and proximal ends of theblood vessel, one or more support structural materials are inserted toreplace damaged blood vessel sections. Some examples of structuralmaterial that can be utilized are described herein at other sections.For example, some non-limiting examples of structural material includeone or more of tubing (such as plastic or rubber tubing, e.g.polyethylene terephthalate or polytetrafluoroethylene), a stent(optionally including one or more therapeutic agents), a matrix (such asextracellular matrix components, or an artificial or synthetic matrix),a rod or other physical support.

Following insertion of the optional support structure, one or more setsof frozen particle compositions are administered to the repaired bloodvessel to secure the structure or assist in modulating hemostasis. Oneor more sets of frozen particle compositions are also optionallyadministered to the junctions between the support structure and thevasculature.

Example 20 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Adhesive Agents and One or More BiologicalRemodeling Agents

Surgical incisions, burns, and other traumatic injuries result in damageto the dermis or hypodermis skin layers. Frozen particles including atleast one adhesive agent, and optionally one or more of a growth factor,an anesthetic, or an antibiotic are administered to the biologicaltissue to secure would closure, including securing skin grafts. Thefrozen particles are administered alone or in conjunction with surgicalstaples or sutures.

In an embodiment, one or more frozen particles including thrombin (e.g.,activated thrombin) or fibrinogen are administered. As described inother sections herein, thrombin and fibrinogen can be included as partof a single frozen particle (including, for example, provided incompartments of a single frozen particle), a single set of frozenparticles, or separately as part of different frozen particles ordifferent sets of frozen particles. As described herein, if multiplesets of frozen particles are administered, the sets can be administeredsimultaneously or sequentially.

In an embodiment, one or more frozen particles including at least oneadhesive agent include a biodegradable polymer that encapsulates atleast one therapeutic agent (such as a growth factor, antibiotic,anesthetic or other agent). For example, poly(∈-caprolactone) (PCL)allows for controlled or sustained release of a therapeutic agent for aspecific location (See, for example, Shenoy et al, Ibid., which isincorporated herein by reference).

In an embodiment, one or more frozen particles include activatedthrombin at a concentration of approximately 0.5 IU/mL, approximately1.0 IU/mL, approximately 1.5 IU/mL, approximately 2.0 IU/mL,approximately 2.5 IU/mL, approximately 3.0 IU/mL, approximately 3.5IU/mL, approximately 4.0 IU/mL, approximately 4.5 IU/mL, approximately5.0 IU/mL, approximately 5.5 IU/mL, approximately 6.0 IU/mL,approximately 6.5 IU/mL, approximately 7.0 IU/mL, approximately 7.5IU/mL, approximately 8.0 IU/mL, approximately 8.5 IU/mL, approximately9.0 IU/mL, or any value therebetween.

In an embodiment, one or more frozen particles include fibrinogen at aconcentration of approximately 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL,60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 115 mg/mL,120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, or any value therebetween.

Since activated thrombin reacts with fibrinogen by way of proteolysis toform a fibrin adhesive, the concentration of either fibrinogen orthrombin can be increased or decreased, depending on the desired goal ofwound closure. (See, e.g., Spotnitz et al. Transfusion, vol. 48, pp.1502-1516 (2008); Evans et al., Braz. J. Urol. vol. 32, pp. 131-141(2006), each of which is incorporated herein by reference.) For example,if a skin graft is involved in the wound repair and a slow rate ofadherence is desired in order to accurately place the graft on thewound, the concentration of either thrombin or fibrinogen can bereduced. Alternatively, separate sets of one or more frozen particlescan be administered, wherein the concentration of at least one adhesiveagent varies within a set or between the separate sets of frozenparticles. Optionally, one or more frozen particles can include at leastone proteolytic inhibitor, such as aprotinin, in order to prolong thefibrin adhesive effect. (See, e.g., Spotnitz et al, Ibid., which isherein incorporated by reference).

Optionally, one or more of the frozen particles includes at least onedetection material (e.g., a non-reactive, biodegradable dye or non-toxiccontrast agent) that allows for visual detection of application of theone or more frozen particles. In an embodiment, the one or more frozenparticles including at least one detection material also include atleast one other agent (e.g., at least one adhesive agent, or at leastone therapeutic agent). (See, e.g., worldwide web atkolorjectchemicals.com/natural-food-color.html, visited on Nov. 25,2008, which is incorporated herein by reference.)

Optionally, frozen particles are administered that include one or moregrowth factor (e.g., keratinocyte growth factor, vascular endothelialgrowth factor A, epidermal growth factor, fibroblast growth factor, orhepatocyte growth factor) to promote engraftment. (See, for example,Nolte et al, Cells Tissue Organs, vol. 187, pp. 165-176 (2008); Boatenget al., J Pharm. Sci. vol. 97, pp. 2892-2923 (2008), each of which isincorporated herein by reference). In addition or instead of thesegrowth factors, one or more frozen particles include one or more ofcollagen, hyaluronic acid, glycosaminoglycans, or other extracellularmatrix components, at least one of which is encapsulated in a PCLpolymer. (See, for example, Boateng et al., Ibid, which is incorporatedherein by reference.)

In an embodiment, compartmentalized frozen particles including one ormore of activated thrombin, fibrinogen, antibiotic (e.g., minocycline,gentamycin, oxoflacin, or tetracycline), or PCL-encapsulatedextracellular matrix or growth factor are administered to a wound.

In an embodiment, one or more frozen particles include one or more cells(e.g., pluripotent stem cells, mesenchymal stem cells, fibroblasts,keratinocytes, dermal progenitor cells) to assist in wound repair,including skin engraftment. For example, dermal fibroblasts suspended incryogenic media (e.g., containing 10% dimethylsulfoxide) are included inone or more frozen particles. In the same or different frozen particle,one or more of at least one growth factor, at least one extracellularmatrix component, or at least one adhesive agent are included.Optionally, one or more of the agents included in the frozen particlesare encapsulated by PCL or another polymer. The frozen particles can beadministered simultaneously or sequentially.

In an embodiment, several different sets of frozen particles areadministered in order to establish layers of, for example, extracellularmatrix, fibroblasts, fibrin sealant, and keratinocytes can beadministered in multiple layers with or without an additional skingraft. In an embodiment, the skin graft itself has been derivedartificially or synthetically, at least in part, by administration offrozen particles including various skin components to at least onebiological tissue or a synthetic matrix (e.g., biodegradable sponge orpolymer matrix).

Optionally, as in the case of burns or other wounds in which necrotictissue is present, frozen particles are administered to debride tissueprior to would closure or skin engraftment. Frozen particles includingone or more of at least one antibiotic (e.g., neomycin, polymixin B, orgramicidin), or at least one anesthetic (e.g., lidocaine). As describedherein at other sections, debridement of cells or tissue is regulated byseveral factors, including characteristics of the one or more frozenparticles (e.g., size, shape, or constitution of any particular frozenparticle), as well as characteristics of administration of the one ormore frozen particles (e.g., velocity of delivery, angle of delivery,quantity of particles delivered, or rate of delivery).

In an embodiment in which tissue is debrided, a device is utilized toadminister the one or more frozen particles, as described herein atother sections. In an embodiment, a tube and nozzle is utilized toadminister the one or more frozen particles, with an optional aspiratortube to remove liquid and tissue as debridement occurs.

Example 21 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Remodeling Agents One or MoreTherapeutic Agents, One or More Adhesive Agents, and One or MoreReinforcement Agents for Tissue Reconstruction

Frozen particle compositions including one or more of a reinforcementagent, antibiotic, therapeutic agent, polymer, adhesive, stem cell, orprogenitor cell are utilized for debriding damaged or necrotic tissue,such as bone and cartilage. Subsequently, one or more frozen particlecompositions as described are utilized for reconstructing the tissue, inaddition to or instead of one or more frozen particle compositionsincluding one or more of a growth factor, progenitor cell or stem cell.

For example, joint restructuring or replacement is a common surgicalprocedure for joints such as knee or hip joints. Knee replacementsurgery is performed as a partial or total knee joint replacement.Standard knee replacement generally includes replacing or supplementingdiseased or damaged joint surfaces with bone grafts (e.g., autologous orcadaveric bone grafts) or synthetic materials (e.g., metal, plastic, orrubber substrates).

Optionally, computer systems are used to model the bone defect, based onimaging studies (e.g., x-ray, computed tomography (CT), or otherimaging). Among other things, imaging the bone or other tissue (e.g.,cartilage), allows for assessment of the defect, or analysis of thepresent joint structure, allows for assistance in designing repair orreplacement of the joint, and provides guidance for delivery of thefrozen particle compositions. In certain instances, the frozen particlecompositions are delivered by way of a piezoelectric or inkjet printerdevice that is directly or indirectly under the control of a computersystem.

In an embodiment, a CT scan is used to develop a three-dimensional imageof the joint to be reconstructed. For a knee joint, for example, regionsfrom the distal femur and proximal tibia, including synovial andcartilage, can be imaged for assessment. Computer systems and methodsfor designing and repairing the joint(s) can also be used for comparingthe present state of the subject's joint with that of a healthyindividual. Thus, the repair may include reconstructing or restructuringthe joint according to healthy or undamaged joints.

Optionally, a computer system also controls a robotic arm or otherautomated instrument containing a piezoelectric or inkjet printerdevice, or sprayer for administration of one or more frozen particlecompositions in the reconstruction of the joint. In certain instances,the subject's damaged or diseased joint is ablated or debrided with oneor more frozen particle compositions in addition to or instead ofreconstructing the joint. In certain instances, one or more frozenparticles are delivered to a substrate (e.g., natural, artificial, orsynthetic materials) used in reconstructing the subject's knee joint. Incertain instances, the substrate includes an artificial knee joint or acadaveric knee joint.

In the case where the subject's joint is ablated or debrided, one ormore frozen particle compositions are administered to the subject'sjoint (optionally with assistance of a computer system). The ablation ordebridement may be performed before, during, or subsequent to theadministration of one or more frozen particle compositions related tostabilizing the joint or reconstructing the joint. For example, frozenparticle compositions including reinforcement agents (e.g., silicabeads, fiberglass, polyethylene glycol) are propelled toward thesubject's knee joint at or to a predetermined velocity that allows fordelivery of the compositions into the various layers of the joint (i.e.,skin, subcutaneous layers, synovial membrane, etc.).

In an embodiment, an arthroscopic device is utilized for delivery of oneor more frozen particle compositions to the knee joint. A computersystem can assist a surgeon in ablating or debriding the cartilageand/or bone to the proper depth by delivering the frozen particlecompositions at a predetermined or preselected set of parameters. Thepredetermined or preselected parameters include, but are not limited to,size of frozen particle compositions, shape of frozen particlecompositions, constitution of frozen particle compositions, velocity atwhich frozen particle compositions are delivered, angle at which frozenparticle compositions are delivered, timing for delivery of specificfrozen particle compositions, or programs for cycling any one or moreparameters. In an embodiment, ablation is performed on a knee joint withguidance provided by a computer system or imaging apparatus. During orsubsequent to ablation, frozen particle compositions containingtherapeutic agents (such as at least one antibiotic or anti-inflammatoryagent) are administered to the joint.

In an embodiment, the joint is reconstructed by utilizing a computersystem for imagine or modeling the joint. Optionally, the computersystem is directly or indirectly linked to a sprayer or piezoelectric orinkjet printer device capable of administering one or more frozenparticle compositions. In certain instances, the frozen particlecompositions administered to reconstruct the joint include scaffoldingmaterials of natural, artificial, or synthetic origin (examples ofspecific agents include, but are not limited to, antibodies; growthfactors; e.g., bone morphogenic protein; polymers; e.g., polylacticacid, polylactic acid-co-glycolic acid; or adhesives; e.g.,polyethylmethacrylate/tetrahydrofurfuryl methacrylate, hydroxyapatite,etc.), or an amphiphilic polymer. In one embodiment, the delivery of oneor more adhesive agents or at least one biological remodeling agents,includes at least one temporally-regulated method. (See, e.g., Davies,et al. Advanced Drug Delivery Reviews, vol. 60, pp. 373-387 (2008); orKanczler et al. Biomaterials, vol. 29, pp. 1892-1900 (2008), each ofwhich is incorporated herein by reference.)

In an embodiment, scaffolding materials solidify in situ atphysiological temperature and pH, and may include, but not be limitedto, calcium phosphate cement with a biocompatible gelling agent andscaffold materials for cartilage regeneration (e.g., oligopoly-ethyleneglycol fumarate, polyN-isopropylacrylamideco-acrylic acid,polyN-isopropylacrylamide-grafted gelatin, polyethylene oxide, alginate,fibrin, PLGA-g-PEG, pluronics, calcium phosphate/hyaluronic acidcomposites, hyaluronic acid gel and chitosan. See, e.g., Hou et al., J.Mat. Chem. vol. 14, pp. 1915-1923 (2004), which is incorporated byreference herein.

Optionally, one or more frozen particle compositions includingscaffolding materials that promote adhesion of cell types that producebone or cartilage are administered to assist in reconstructing thesubject's joint. For example, integrin peptides with thearginine-glycine-aspartic acid (RGD) sequence can be covalently coupledwith other scaffolding materials administered to the joint. Integrinsare capable of promoting adhesion of cells, including osteoblasts, viatheir integrin receptors. See, e.g., Hou, et al., Ibid.

Optionally, one or more frozen particle compositions includingantibodies or antibody fragments are chemically coupled with scaffoldpolymers that among other things, promote binding and retention ofspecific cell types within the scaffold, are administered to thesubject's knee or a substrate used in reconstructing the knee. Forexample, anti-integrin α_(V)β₃ antibodies recognize endothelial cells,and anti-integrin α₅ antibodies recognize chondrocytes, both of whichcell types can assist in reconstructing the joint. See, e.g., Hou et al,Ibid.

Optionally, one or more frozen particle compositions including one ormore growth factors that are capable, for example, of promoting cellgrowth and/or cell differentiation are administered in reconstructingthe knee joint. For example, bone morphogenic proteins, fibroblastgrowth factors, vascular endothelial growth factors, or other factorsare encapsulated in polymer particles (e.g., vesicles) that form atleast part of a scaffold to support reconstruction of the joint. See,e.g., Davies et al., Ibid. In an embodiment, one or more growth factorssupport the infiltration or growth of osteocytes, chondrocytes, orvascular cells.

In an embodiment, one or more frozen particle compositions including oneor more of a progenitor cell, stem cell, osteoblast, chondrocyte, orendothelial cell are administered. In an embodiment, one or more subsetsof frozen particle compositions include, but are not limited tocompositions containing one or more of a scaffolding material, adhesiveagent, or growth factor. In an embodiment, one or more subsets of frozenparticle compositions are administered to the subject's jointsimultaneously, sequentially, or cyclically.

In an embodiment, reconstruction of the joint is conducted byadministering one or more subsets of frozen particle compositionsthrough interaction or consultation with a computer system. In anembodiment, administration of one or more frozen particle compositionsor one or more subsets of frozen particle compositions occurs in astepwise fashion according to one or more parameters including, but notlimited to, size of frozen particle compositions, shape of frozenparticle compositions, constitution of frozen particle compositions,velocity at which frozen particle compositions are delivered, angle atwhich frozen particle compositions are delivered, timing for delivery ofspecific frozen particle compositions, or programs for cycling any oneor more parameters.

In an embodiment, the joint is debrided, and the surface is prepared forreconstruction. Additionally, one or more frozen particle compositionsor one or more subsets of frozen particle compositions are administeredcontaining one or more of a scaffolding material, an adhesive agent, atherapeutic agent, a reinforcement agent, or an explosive agent. Forexample, calcium phosphate cement with a biocompatible gelling agent areincluded with one or more frozen particle compositions. In the same ordifferent frozen particle compositions, growth factors (such as vascularendothelial growth factors or bone morphogenic factors) are included. Inaddition, in the same or different frozen particle compositions,osteoblast cells or osteoblast precursor cells are administered to thesubject's joint or a substrate used for reconstructing the joint. In thesame or different frozen particle compositions, at least one scaffoldmaterial, such as a polymer, is administered to the joint or a substrateused for reconstructing the joint. For example, oligopoly-ethyleneglycol fumarate optionally with a chondrocyte growth factor (e.g.,fibroblast growth factor) are included in one or more frozen particlecompositions. In the same or different frozen particle compositions,frozen particle compositions including chondrocytes or condrocyteprogenitor cells (e.g., mesenchymal stem cells) are administered to thejoint.

In an embodiment, one or more steps of assessing the joint, preparingthe joint, debriding or abrading the joint, or reconstructing the jointare aided by use of a computer system, including but not limited to CTimaging, computer-aided design (CAD), or computer-aided surgery (CAS).See, e.g., Bradley et al., Arch. Otolaryngol. Head Neck Surg. Vol. 34,pp. 1080-1084 (2008), which is incorporated by reference herein.

Example 22 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Adhesive Agents and One or MoreBiological Remodeling Agents

Frozen particles containing one or more biological adhesive agents (forexample, bispecific antibodies or bispecific proteins), are used to bindcells or tissues specifically to therapeutic targets, such asendothelial cells, leukocytes, epithelial cells, cancer cells,extracellular matrices, vasculature, lymphatics, tumors, and othertissues. For example, one or more frozen particles containing at leastone bispecific receptor, antibody, ligand, or fusion proteins of one ormore of receptors, antibodies, or ligands are used to selectively bindor adhere leukocytes, such as macrophages, monocytes, T cells, naturalkiller cells (NK cells), granulocytes, or other cells to target tissues,extracellular matrices, or other cell types (e.g., cancer cells,endothelial cells, or epithelial cells).

Moreover, one or more frozen particles optionally contain at least onebiological adhesive agent and at least one leukocyte in separatesectors. In one embodiment, the sector includes a compartment.

In one embodiment, one or more biological adhesive agent is bound to aleukocyte (or other cell) in vitro prior to incorporation of the cellplus biological adhesive into the one or more frozen particlecompositions. Optionally, one or more frozen particle compositionsincluding at least one biological adhesive or at least one cell aredelivered sequentially to a target tissue, matrix, or cell type.

Examples of one or more biological adhesive agents are disclosed hereinat other sections, and include but are not limited to mammalian cellsurface proteins, and glycoproteins. For example, adhesion moleculesinclude CD44, immunoglobulin (Ig) superfamily members, integrins,cadherins, and selectins. These or other factors that are included inthe disclosure specifically bind to protein or macromolecule ligands(e.g., intercellular adhesion molecule (ICAM), vascular cell adhesionmolecule (VCAM), fibronectin, and hyaluronate), MADCAM, LFA-1, andothers. Other cell surface receptors are included as biological adhesiveagents, including but not limited to immunoglobulin Fc receptors (FcR),complement receptors (CR), and surface immunoglobulin (sIg).

Example 23 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Adhesive Agents for Administration toTumor Tissue

Frozen particles containing one or more biological-based adhesive agentsare used to deliver and bind immune effector cells to primary ormetastatic tumor cells, as well as tumor-associated stroma orextracellular matrices. Macrophages or monocytes that have the potentialto kill tumor cells, and present tumor-associated antigens arerecognized by antibodies that bind integrin receptors, such as VLA-4,β-1, β-2, Fcγ receptor I (CD64) or by cell adhesion peptides (e.g.,YRGDS, YEILDV). (See, for example, Martin-Manso et al., Cancer Res.,vol. 68, pp. 7090-7099 (2008); Wagner et al., Biomat., vol. 25, pp.2247-2263 (2006); each of which is incorporated herein by reference). Inaddition, lymphocytes (such as T cells or B cells), as well as naturalkiller cells are capable of directed killing of tumor cells, and areincluded in specific embodiments disclosed herein.

Biological adhesive agents, including a bispecific antibody, such asanti-CD64 binding domain (e.g., single chain Fv (SCFv)) is fused to asecond binding domain that recognizes a tumor-associated antigen (e.g.,CA-125 (mucin 16), or melanoma-associated antigen (MAGE)). Mucin 16binds macrophages to ovarian cancer cells, while MAGE binds macrophagesto melanoma cancer cells. Generation, including design, construction,and production, of bispecific antibodies is generally known in the art.(See, for example, USPTO Application Publication No. 20080305105; Kuferet al., Trends in Biotech., vol. 22, pp. 238-244 (2004); each of whichis incorporated herein by reference.)

Macrophage or monocyte cells are obtained from the peripheral blood ofcancer patients or subjects. Monocytes are purified from peripheralblood leukocytes (standard reagents and protocols are available from,for example, StemCell Tech., Inc., Vancouver, B.C., Canada). Monocytesare activated by treatment in vitro with cytokines, such asinterferon-γ. (See, for example, Kufer et al., Ibid.) Production ofmacrophage cells that are cytotoxic for tumor cells is described, forexample, in Martin-Manso et al., Ibid. Cytotoxic macrophage cells arebound in vitro to a bispecific antibody (e.g., antibody that recognizesCD64 or MAGE), prior to incorporation into one or more frozen particlecompositions for administration to a melanoma tumor.

Briefly, bispecific antibodies at 10-100 micrograms/mL in RPMI 1640media, pH 7.4 (Invitrogen Corp., Carlsbad, Calif.), are incubated withmonocyte cells for 1-4 hours at 5°-37° C. Monocyte cells with boundbispecific antibodies are washed by centrifugation and incorporated intoone or more frozen particle compositions containing dimethylsulfoxide(10% vol/vol), RPMI 1640 media, and human serum (20% vol/vol).

One or more frozen particle compositions containing one or more monocytecells, one or more biological adhesive agents, and media are delivereddirectly to tumor tissue by a device (for example, a spray device).Depending on various factors, including but not limited to, size oftumor, presence of metastatic tumor tissue, extent of any metastatictissue, type of tissue of origin for the tumor, location of tumor,condition of the subject, or other factors, the depth of frozen particlepenetration can be predicted or determined through design or alterationof frozen particle composition velocity, size, shape, and constituencyof the one or more frozen particles.

Example 24 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Adhesive Agents for Administration toTumor Tissue

Immune effector cells (including monocytes, macrophages, natural killercells, or lymphocytes) plus bound bispecific antibodies are delivered totumor tissue, for example, at a site or organ (e.g. lung, liver) using adevice (such as an endoscope, including a laparascope or thoracoscope).In one embodiment, a particle spraying device is introduced through atrocar and guided by way of an endoscope, delivers the frozen particlecompositions including at least one immune effector cell with at leastone biological adhesive to the target site. In one embodiment, thetarget site includes tumor tissue. In at least on embodiment, the targetsite includes tissue surrounding a tumor. In one embodiment, the targetsite includes tissue suspected of being cancerous. In one embodiment,the target site includes primary tumor tissue. In one embodiment, thetarget site includes metastatic cancer tissue.

In one embodiment, frozen particle compositions including at least onebiological adhesive and at least one immune effector cell areadministered as an adjunct therapy following surgery to resect diseasedtissue, chemotherapy, radiation treatment, or other therapy. Forexample, frozen particle compositions including at least one biologicaladhesive that recognizes monocytes (e.g., anti-CD64) and MAGE areadministered to tissue surrounding the surgical site, including lymphnodes or sites of suspected or anticipated metastasis.

Example 25 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Adhesive Agents to Melanoma Cells andTumor-Associated Endothelial Cells

At least one biological adhesive recognizing one or more integrinpresent on melanoma cells or tumor endothelial cells is used to bindimmune effector cells to melanoma cells or tumor-associated endothelialcells. For example, one or more antibodies specific for the integrinα_(v)β₃ and CD3 (a signaling part of the T cell antigen receptor) can beused in conjunction with cytotoxic T cells derived from melanomasubjects. See, for example, Berger et al., J. Clin. Invest. vol. 118,pp. 294-305 (2008), which is incorporated herein by reference.

One or more frozen particle compositions containing anti-α_(v)β₃,anti-CD3, or cytotoxic T cells bind to melanoma cells directly orindirectly following binding to tumor neovasculature endothelium andextravasation. See, for example, Mahabeleshwar et al., Ibid. In oneembodiment, the one or more frozen particle compositions areadministered in multiple dimensions (e.g., x, y, z coordinates) tomelanoma cells, neovasculature, and adjacent tissues (which may or maynot be malignant). In one embodiment, primary tumor cells, metastatictumor cells, neovasculature, and adjacent lymphatic ducts and lymphnodes are targeted. One or more frozen particle compositions deliveredto the epidermis, dermis, and subcutaneous layers of a subject targetmelanoma cells in radial, vertical, and metastatic modes of growth. See,for example, Mahabeleshwar et al, Ibid.

In one embodiment, administration of the one or more frozen particlecompositions in three dimensions is conducted with a computer-guidedspraying device. The computer-guided device uses one or more computersystems, or one or more computer programs to derive or obtain data topredict or generate one or more frozen particle compositions based onspecific characteristics. For example, the one or more frozen particlecompositions are predicted or generated based on particle hardness,shape, size, constituency, or other factors. The one or more frozenparticle composition administration is predicted or generated based onnumber of frozen particle compositions administered for any particularround of delivery, the velocity of delivery, the angle of delivery, thenumber of rounds of delivery of the same or different frozen particlecompositions, the type of tissue receiving the frozen particlecompositions, the condition of the tissue receiving the frozen particlecompositions, and other factors. In this manner, the one or more frozenparticle compositions are administered to a particular target tissue,and to a particular desired depth or breadth.

Example 26 Compositions and Methods of Administering Frozen ParticlesIncluding One or More Biological Adhesive Agents to Melanoma Cells

One or more frozen particle compositions including one or morebiological adhesive agents capable of specifically binding melanomatumor cell surface receptors, including at least one receptor capable ofsignaling or initiating apoptosis are administered to melanoma cells.For example, at least one biological adhesive agent including at leastone bispecific protein that recognizes melanoma tumor cell antigens(e.g., MAGE), as well as a pro-apoptotic cell surface receptor (e.g.,death receptor 5 (DR5)) is delivered to melanoma cells for induction ofapoptosis.

In one embodiment, binding of DR5 by an agonistic monoclonal antibody orapoptosis ligand 2/TNF-related apoptosis-inducing ligand (e.g.,Apo2L/TRAIL) initiates signaling that leads to apoptotic death of thetumor cell. See, for example, Ashkenazi, Nat. Rev. Drug Discov., vol. 7,pp. 1001-1012 (2008). Some examples of agonistic antibodies that arecapable of inducing apoptosis on tumor cells include, but are notlimited to, mapatumumab and lexatumumab (Human Genome Sciences, Inc.,Rockville, Md.; HGS), Apomab (Genentech Inc., South San Francisco,Calif.), AMG655 (Amgen, Inc., Thousand Oaks, Calif.), CS-1008 (DaiichiSankyo Co., Ltd., Tokyo), and LBY-135 (Novartis Int'l AG, Basel).

In one embodiment, a bispecific protein including anti-MAGE bindingdomains (e.g., single chain Fv (SCFv)) and at least one agonisticanti-DR5 binding domain (e.g., SCFv from Apomab; Ashkenazi, Ibid) isadministered in one or more frozen particle compositions directly tomelanoma cells, or delivered to subcutaneous layers surround themelanoma cells.

In one embodiment, in addition to targeting primary tumor cells, tissueknown to be metastatic, or suspected to be metastatic due to theepidemiology of the disease, are targeted. For example, melanoma isknown to metastasize to the brain. In one embodiment, the brain receivesone or more frozen particles alone or in combination with surgery (e.g.,craniotomy), based on imaging studies done with computer-assistedtomography or magnetic resonance imaging. Frozen particle compositionsincluding pro-apoptotic agonists or anti-MAGE binding proteins are usedas adjuvant therapy following surgery (e.g., open surgery, stereotacticsurgery, or stereotactic radiosurgery to remove or destroy melanomametastatic cells.

In one embodiment, minimally invasive computer assisted surgery is usedto remove tumor cells and tumor tissue, followed by administration ofone or more frozen particle compositions as adjuvant therapy. Forexample, computer-aided surgery (CAS) is used with stereotactic surgerysystems to target tumor cells that have infiltrated essential and/orhighly vascularized brain tissues that are considered inaccessible orinoperable by standard methods.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to those skilled inthe art that, based upon the teachings herein, changes and modificationscan be made without departing from the subject matter described hereinand its broader aspects and, therefore, the appended claims are toencompass within their scope all such changes and modifications as arewithin the true spirit and scope of the subject matter described herein.It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to claims containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that typically a disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms unless context dictates otherwise. For example, the phrase “Aor B” will be typically understood to include the possibilities of “A”or “B” or “A and B.”

With respect to the appended claims, those skilled in the art willappreciate that recited operations therein may generally be performed inany order. Also, although various operational flows are presented in asequence(s), it should be understood that the various operations can beperformed in other orders than those which are illustrated, or can beperformed concurrently. Examples of such alternate orderings may includeoverlapping, interleaved, interrupted, reordered, incremental,preparatory, supplemental, simultaneous, reverse, or other variantorderings, unless context dictates otherwise. Furthermore, terms like“responsive to,” “related to,” or other past-tense adjectives aregenerally not intended to exclude such variants, unless context dictatesotherwise.

All publications and patent applications cited in this specification areincorporated herein by reference to the extent not inconsistent with thedescription herein and for all purposes as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference for all purposes.

What is claimed is:
 1. A method for providing at least one adhesiveagent to at least one substrate, comprising: administering at least onefrozen particle composition to at least one substrate at a predeterminedvelocity, wherein the at least one frozen particle composition includesone or more frozen hydrogen oxide particles coated in at least oneadhesive agent; wherein the at least one adhesive agent includes one ormore epoxy adhesive, acrylic adhesive, urethane adhesive, polyurethaneadhesive, anerobic adhesive, urethane acrylate, polyester acrylate,methyacrylate, or cyanoacrylate.
 2. The method of claim 1, wherein theat least one adhesive agent includes at least one of a monomer,prepolymer, polymer, or copolymer.
 3. The method of claim 1, wherein thesubstrate includes at least a portion of which is naturally,artificially, or synthetically derived.
 4. The method of claim 1,wherein the substrate includes at least a portion of which isgenetically altered.
 5. The method of claim 1, wherein the at least onesubstrate includes one or more of a cell, tissue, organ, structure, ordevice.
 6. The method of claim 5, wherein the structure includes one ormore of a prosthesis, cell matrix, or tissue matrix.
 7. The method ofclaim 1, wherein the at least one substrate is located in at least oneof in situ, in vitro, in vivo, in utero, in planta, or ex vivo.
 8. Themethod of claim 7, wherein the at least one substrate is transplanted orimplanted into at least one subject.
 9. The method of claim 7, whereinthe at least one substrate is ingested by at least one subject.
 10. Themethod of claim 7, wherein the at least one substrate includes at leastone biological tissue from at least one donor or recipient.
 11. Themethod of claim 1, wherein the at least one substrate includes one ormore wounds.
 12. The method of claim 1, further including varying therate, velocity, or angle at which the at least one frozen particlecomposition is administered to at least one substrate.
 13. The method ofclaim 1, further including administering to the at least one substrateat least one of a nanoparticle, detection material, sensor,micro-syringe, or circuit.
 14. The method of claim 1, wherein the atleast one frozen particle composition further includes one or more of areinforcement agent, abrasive, explosive material, or biologicalremodeling agent.
 15. The method of claim 1, wherein the at least oneadhesive agent further includes at least one α-cyanoacrylate and afluorescent compound including at least one of a bis-benzoxazolylcompound, pyrylium salt, quantum dot, or coumarin compound.
 16. Themethod of claim 1, wherein the at least one adhesive agent furtherincludes an α-cyanoacrylate and2,5-bis-(5-tert-butyl-2-benzoxasolyl)-thiophene.
 17. The method of claim1, wherein the at least one adhesive agent further includes one or moreof a base component, initiator component, or activator component. 18.The method of claim 1, wherein the at least one adhesive agent furtherincludes at least one curing component.
 19. A method of maintaining theapproximation of tissue of at least one wound of a subject, comprising:administering at least one frozen particle composition to at least onewound of a subject at a predetermined velocity, for a time sufficient tomaintain the approximation of tissue of the at least one wound; whereinthe at least one frozen particle composition includes one or more frozenhydrogen oxide coated in at least one adhesive agent; wherein the atleast one adhesive agent; wherein the at least one adhesive agentincludes one or more epoxy adhesive, acrylic adhesive, urethaneadhesive, polyurethane adhesive, anerobic adhesive, urethane acrylate,polyester acrylate, methyacrylate, or cyanoacrylate; and wherein the oneor more frozen hydrogen oxide particles have one or more phasesincluding at least one of amorphous solid water, low density amorphousice, high density amorphous ice, very high density amorphous ice,clathrate ice, hyperquenched glassy water, ice Ic, ice II, ice III, iceIV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, ice XII,ice XIII, ice XIV, or ice XV.